A systematic review of rye (Secale cereale L.) as a source of resistance to pathogens and pests in wheat (Triticum aestivum L.).
Wheat is globally one of the most important crops. With the current human population growth rate, there is an increasing need to raise wheat productivity by means of plant breeding, along with development of more efficient and sustainable agricultural systems. Damage by pathogens and pests, in combination with adverse climate effects, need to be counteracted by incorporating new germplasm that makes wheat more resistant/tolerant to such stress factors. Rye has been used as a source for improved resistance to pathogens and pests in wheat during more than 50 years. With new devastating stem and yellow rust pathotypes invading wheat at large acreage globally, along with new biotypes of pest insects, there is renewed interest in using rye as a source of resistance. Currently the proportion of wheat cultivars with rye chromatin varies between countries, with examples of up to 34%. There is mainly one rye source, Petkus, that has been widely exploited and that has contributed considerably to raise yields and increase disease resistance in wheat. Successively, the multiple disease resistances conferred by this source has been overcome by new pathotypes of leaf rust, yellow rust, stem rust and powdery mildew. However, there are several other rye sources reported to make wheat more resistant to various biotic constraints when their rye chromatin has been transferred to wheat. There is also development of knowledge on how to produce new rye translocation, substitution and addition lines. Here we compile information that may facilitate decision making for wheat breeders aiming to transfer resistance to biotic constraints from rye to elite wheat germplasm.


Correlational selection and the evolution of genomic architecture.
We review and discuss the importance of correlational selection (selection for optimal character combinations) in natural populations. If two or more traits subject to multivariate selection are heritable, correlational selection builds favourable genetic correlations through the formation of linkage disequilibrium at underlying loci governing the traits. However, linkage disequilibria built up by correlational selection are expected to decay rapidly (ie, within a few generations), unless correlational selection is strong and chronic. We argue that frequency-dependent biotic interactions that have 'Red Queen dynamics' (eg, host-parasite interactions, predator-prey relationships or intraspecific arms races) often fuel chronic correlational selection, which is strong enough to maintain adaptive genetic correlations of the kind we describe. We illustrate these processes and phenomena using empirical examples from various plant and animal systems, including our own recent work on the evolutionary dynamics of a heritable throat colour polymorphism in the side-blotched lizard Uta stansburiana. In particular, male and female colour morphs of side-blotched lizards cycle on five- and two-generation (year) timescales under the force of strong frequency-dependent selection. Each morph refines the other morph in a Red Queen dynamic. Strong correlational selection gradients among life history, immunological and morphological traits shape the genetic correlations of the side-blotched lizard polymorphism. We discuss the broader evolutionary consequences of the buildup of co-adapted trait complexes within species, such as the implications for speciation processes.


Advanced virtual reality-based rehabilitation of balance and gait in clinical practice.
Extensive research shows that virtual reality (VR) enhances motor learning and has advantages in balance and gait rehabilitation of neurological patients. There is still uncertainty, however, as for the practicality and efficacy of VR in long-term clinical routine. The objective of this study was to report on 3 years of clinical practice conducting VR-based rehabilitation of balance and gait in a large medical center. This retrospective study systematically analyzed clinical records of patients who received VR-based rehabilitation in a large rehabilitation center during 3 years. We evaluated the effect of VR-based rehabilitation treatments on balance and gait, cognitive dual-task load, patient's balance confidence (ABC-scale) and perception of suitability. Patients were either neurological patients, allocated to five groups: Parkinson's disease (PD), poststroke (PS), multiple sclerosis, traumatic brain injury, and 'other conditions', or non-neurological patients. Records of 167 patients were analyzed. The availability of multiple VR systems and environments contributed to highly personalized interventions that tailored specific deficits with therapeutic goals. VR-based rehabilitation significantly improved balance and gait (measured by 10-Meter Walk Test, Timed-Up-and-Go, Berg Balance Scale, and Mini BESTest). Patients with PD and PS decreased dual-task cost while walking. Patients increased balance confidence and deemed VR suitable for rehabilitation. Our results suggest that VR-based rehabilitation is practicable and effective in clinical routine. Functional measures of balance and gait show significant improvements following VR-based interventions. Clinical approaches should exploit VR advantages for promoting motor learning and motivation. This study serves to aid transition to long-term clinical implementation of VR.


Study design and participation rates of the New York City Health and Nutrition Examination Survey, 2004.
Few state or local health agencies have accurate local-level information on the prevalence of the leading causes of morbidity and mortality. The New York City Health and Nutrition Examination Survey (NYC HANES) was designed as a new local surveillance initiative to determine the prevalence of health conditions among adult residents of New York City. Modeled after the National Health and Nutrition Examination Survey, the survey was initiated in June 2004 as a population-based cross-sectional study of New York City adults aged 20 and older. The survey was designed using a three-stage cluster sampling plan; 4026 households were randomly selected. Selected households were visited, and residents were given an initial eligibility screening questionnaire. Eligible participants were asked to schedule an appointment at an NYC-HANES-dedicated health center to complete the NYC HANES. A completed survey was defined as completion of a demographic interview and at least one examination component. Health conditions examined included cholesterol levels, diabetes status, blood pressure, environmental biomarkers, depression, anxiety, and antibodies to infectious diseases. Of the 4026 households approached, eligibility screening questionnaires were completed for 3388 (84%) households, and 3047 survey participants were identified. Of the 3047 participants, 76% made an appointment, and 66% completed the survey. The overall response rate was 55% (n = 1999). NYC HANES is the first successful local-level examination survey modeled on NHANES. With periodic repetition, NYC HANES will provide surveillance information on leading causes of morbidity and mortality.


The modern histopathologist: in the changing face of time.
The molecular age histopathologist of today is practicing pathology in a totally different scenario than the preceding generations did. Histopathologists stand, as of now, on the cross roads of a traditional 'visible' morphological science and an 'invisible' molecular science. As molecular diagnosis finds more and more applicability in histopathological diagnosis, it is time for the policy makers to reframe the process of accreditation and re-accreditation of the modern histopathologist in context to the rapid changes taking place in this science. Incorporation of such 'molecular' training vis-a-vis information communication technology skills viz. telemedicine and telepathology, digital imaging techniques and photography and a sound knowledge of the economy that the fresh entrant would ultimately become a part of would go a long way to produce the Modern Histopathologist. This review attempts to look at some of these aspects of this rapidly advancing 'art of science.'


Type 1 diabetes incidence and prevalence trends in a cohort of Canadian children and youth.
Incidence rates of type 1 diabetes have long been on the rise across the globe, however, there is emerging evidence that the rate of rise may be slowing. The objective of this study was to describe trends in the incidence and prevalence of type 1 diabetes in a sample of Canadian children and youth. Cases were extracted using linked administrative datasets and a validated diabetes case-finding definition. Incidence and prevalence trends were analyzed using the JoinPoint regression analysis program. A small increase in the incidence of type 1 diabetes was observed over the 11-year period from 2002-2003 to 2012-2013. Total incident cases per year ranged from 201 (2005-2006) to 250 (2007-2008). Total prevalent cases per year ranged from 1790 (2002-2003) to 2264 (2012-2013). Incidence was highest among children aged 5 to 14 years, and lowest in the youngest (1-4 years) and oldest (15-19 years) age brackets. The most significant increase in incidence was in children aged 10 to 14 years. Age-standardized prevalence increased significantly throughout the study period. These results are similar to data from the United States but differ from European data with respect to the annual percent change for incidence as well as age-specific incidence trends. In keeping with the low mortality rates associated with type 1 diabetes, the prevalence continues to rise.


Cannabis in the external ear.
ENT surgeons may well be asked to remove cannabis from the external ear where it has been lodged for various reasons. We report two cases and review four other cases we found in the literature to illustrate some of the difficulties. It is important that anyone working with people who abuse drugs are aware that cannabis can be concealed in the external ear.


Cerebral aneurysm coiling: a predictive model of hospitalization cost.
Several initiatives have been put in place to minimize healthcare expenditures. In new and evolving fields such as endovascular aneurysm treatment, there are limited data to support such measures. The objective of the present study was to develop and validate a predictive model of hospitalization cost after cerebral aneurysm coiling (CACo). We performed a retrospective study involving CACo patients who were registered in the Nationwide Inpatient Sample database from 2005 to 2010. The cohort underwent 1:1 randomization to create derivation and validation subsamples. Regression techniques were used for the creation of a parsimonious predictive model. Of the 10,928 patients undergoing CACo, 6617 (60.5%) presented with unruptured and 4311 (39.5%) with ruptured aneurysms. Median hospitalization cost was US$35,446 (IQR $13,801-$57,091). Common drivers of cost identified in the multivariate analysis included: length of stay; number of admission diagnoses and procedures; hospital size and region; patient income; hydrocephalus; acute renal failure; and seizures. The model was validated in independent cohorts and demonstrated a final R(2) value very similar to the initial model. The predicted and observed values in the validation cohort demonstrated good correlation. This national study identified significant drivers of hospitalization cost after CACo. The presented model can be utilized as an adjunct in the cost containment debate and the creation of data driven policies.


Disorders of compulsivity: a common bias towards learning habits.
Why do we repeat choices that we know are bad for us? Decision making is characterized by the parallel engagement of two distinct systems, goal-directed and habitual, thought to arise from two computational learning mechanisms, model-based and model-free. The habitual system is a candidate source of pathological fixedness. Using a decision task that measures the contribution to learning of either mechanism, we show a bias towards model-free (habit) acquisition in disorders involving both natural (binge eating) and artificial (methamphetamine) rewards, and obsessive-compulsive disorder. This favoring of model-free learning may underlie the repetitive behaviors that ultimately dominate in these disorders. Further, we show that the habit formation bias is associated with lower gray matter volumes in caudate and medial orbitofrontal cortex. Our findings suggest that the dysfunction in a common neurocomputational mechanism may underlie diverse disorders involving compulsion.


Geographic bias of field observations of soil carbon stocks with tropical land-use changes precludes spatial extrapolation.
Accurately quantifying changes in soil carbon (C) stocks with land-use change is important for estimating the anthropogenic fluxes of greenhouse gases to the atmosphere and for implementing policies such as REDD (Reducing Emissions from Deforestation and Degradation) that provide financial incentives to reduce carbon dioxide fluxes from deforestation and land degradation. Despite hundreds of field studies and at least a dozen literature reviews, there is still considerable disagreement on the direction and magnitude of changes in soil C stocks with land-use change. We conducted a meta-analysis of studies that quantified changes in soil C stocks with land use in the tropics. Conversion from one land use to another caused significant increases or decreases in soil C stocks for 8 of the 14 transitions examined. For the three land-use transitions with sufficient observations, both the direction and magnitude of the change in soil C pools depended strongly on biophysical factors of mean annual precipitation and dominant soil clay mineralogy. When we compared the distribution of biophysical conditions of the field observations to the area-weighted distribution of those factors in the tropics as a whole or the tropical lands that have undergone conversion, we found that field observations are highly unrepresentative of most tropical landscapes. Because of this geographic bias we strongly caution against extrapolating average values of land-cover change effects on soil C stocks, such as those generated through meta-analysis and literature reviews, to regions that differ in biophysical conditions.


Seasonal and annual changes in PAH concentrations in a remote site in the Pacific Ocean.
This paper reports the long term observation of particle-associated polycyclic aromatic hydrocarbons (PAHs) at Cape Hedo Atmosphere and Aerosol Monitoring Station, a remote site in the Western Pacific Ocean, from 2008 to 2015. This is the first long-term study that evaluated the contribution of long-range transport of PAHs in East Asia. No obvious trend (P > 0.05) was found in a particular season over the years. However, there are seasonal variations of PAH concentrations with higher in spring and winter. The higher PAH are attributed to air masses from the area including part of China. Source apportionment using three different approaches, i.e., PAH compositional pattern analysis, PAH diagnostic ratio analysis and positive matrix factorization modeling, showed the combined high contribution of biomass burning (18%, 14%) and coal combustion (33%, 24%) in spring and winter. In addition, the contribution of ship emissions (35%) was relatively high in spring, whereas that of vehicle emissions (36%) was relatively high in winter. The contribution of coal combustion to PAH has decreased throughout the years, likely due to changes in energy structure in China. The contribution of biomass burning to PAH has showed no trend, being stable, and that of vehicular emissions has increased.


Type II secretion system of Pseudomonas aeruginosa: in vivo evidence of a significant role in death due to lung infection.
The role of toxins secreted by the type II secretion system (T2SS) of Pseudomonas aeruginosa during lung infection has been uncertain despite decades of research. Using a model of pneumonia in Toll-like receptor (TLR) 2,4(-/-) mice, we reexamined the role of the T2SS system. Flagellin-deficient mutants of P. aeruginosa, with mutations in the T2SS and/or T3SS, were used to infect mice. Mice were followed up for survival, with some killed at different intervals to study bacterial clearance, inflammatory responses, and lung pathology. Strains carrying either secretion system were lethal for mice. Double mutants were avirulent. The T3SS(+) strains killed mice within a day, and the T2SS(+) strains killed them later. Mice infected with a strain that had only the T2SS were unable to eradicate the organism from the lungs, whereas those infected with a T2SS-T3SS double deletion were able to clear this mutant. Death caused by the T2SS(+) strain was accompanied by a >50-fold increase in bacterial counts and higher numbers of viable intracellular bacteria. The T2SS of P. aeruginosa may play a role in death from pneumonia, but its action is delayed. These data suggest that antitoxin strategies against this organism will require measures against the toxins secreted by both T2SS and T3SS.


Efficacy of fingolimod and interferon beta-1b on cognitive, MRI, and clinical outcomes in relapsing-remitting multiple sclerosis: an 18-month, open-label, rater-blinded, randomised, multicentre study (the GOLDEN study).
Cognitive impairment (CI) affects 40-65% of multiple sclerosis (MS) patients. This study attempted evaluating the effects of fingolimod and interferon beta-1b (IFN β-1b) on CI progression, magnetic resonance imaging (MRI) and clinical outcomes in relapsing-remitting MS (RRMS) patients over 18 months. The GOLDEN study was a pilot study including RRMS patients with CI randomised (2:1) to fingolimod (0.5 mg daily)/IFN β-1b (250 µg every other day). CI was assessed via Rao's Brief Repeatable Battery and Delis-Kaplan Executive Function System test. MRI parameters, Expanded Disability Status Scale scores and relapses were measured. Overall, 157 patients were randomised, of whom 30 discontinued the study (fingolimod, 8.49%; IFN β-1b, 41.18%; p ≤ 0.0001). Patients randomised to fingolimod had more severe clinical and MRI disease characteristics at baseline compared with IFN β-1b. At Month (M) 18, both treatment groups showed improvements in all cognitive parameters. At M18, relapse rate, total number and volume of T2/T1 gadolinium-enhancing lesions were higher with IFN β-1b, as well as the percentage brain volume change during the study. Safety and tolerability of both treatments were similar to previous studies. Both treatments showed improvements in cognitive parameters. Fingolimod demonstrated significantly better effects on MRI parameters and relapse rate. Imbalance in baseline characteristics and the drop-out pattern may have favoured IFN β-1b. A longer duration trial may be needed to observe the complete expression of differential effects on CI scales reflecting the between-groups differences on MRI. Although limited in size, the GOLDEN study confirms the favourable benefit-risk profile of fingolimod reported in previous studies.


Clostridium difficile Infection in Production Animals and Avian Species: A Review.
Clostridium difficile is the leading cause of antibiotic-associated diarrhea and colitis in hospitalized humans. Recently, C. difficile infection (CDI) has been increasingly recognized as a cause of neonatal enteritis in food animals such as pigs, resulting in stunted growth, delays in weaning, and mortality, as well as colitis in large birds such as ostriches. C. difficile is a strictly anaerobic spore-forming bacterium, which produces two toxins A (TcdA) and B (TcdB) as its main virulence factors. The majority of strains isolated from animals produce an additional binary toxin (C. difficile transferase) that is associated with increased virulence. C. difficile is ubiquitous in the environment and has a wide host range. This review summarizes the epidemiology, clinical presentations, risk factors, and laboratory diagnosis of CDI in animals. Increased awareness by veterinarians and animal owners of the significance of clinical disease caused by C. difficile in livestock and avians is needed. Finally, this review provides an overview on methods for controlling environmental contamination and potential therapeutics available.


Meal replacements for weight loss in type 2 diabetes in a community setting.
Background. There is limited information on the effectiveness of meal replacements (MRs) as a weight-loss strategy in an unsupervised community setting. Aim. To evaluate the use of MR compared with a diet book for 6 months. Subjects and Methods. Obese subjects (n = 120) with type 2 diabetes mellitus were recruited from the community in Adelaide, South Australia, and randomised to intervention or control. Subjects in the intervention were advised to consume 2 MR/day for 3 months and 1 MR/day for 3 months and follow the manufacturers' instructions from printed material and the website. Subjects in the control arm were given a commercially available diet book. Results. Consumption of 2 MR for 3 months and 1 MR for the subsequent 3 months led to weight loss of 5.5 kg (5%) and a 0.26% decrease in HbA1c while the diet book group had a weight loss of 3 kg (3%) (P = 0.027 for difference between groups) and a decrease in HbA1c of 0.15% (between group ns) in those who completed the 6-month study. On intention-to-treat (last observation carried forward) weight loss at 6 months was 3.4 kg in MR and 1.8 kg in control (P = 0.07). Decreases in HbA1c were 0.22% and 0.12%, respectively (P = ns). HDL cholesterol increased by 4% in MR and decreased by 1% in control (P = 0.004). Blood pressure decreased equally in both groups. There were reductions in fasting glucose in both groups at 6 months with no changes in LDL-cholesterol or triglyceride concentrations. Conclusion. MR confers benefits in HbA1C reduction and weight loss at 6 months in those who completed the study.


Influence of ultrasound on the heterogeneous Fenton-like oxidation of acetic acid.
The main objective of this study is to investigate the effect of ultrasound on the heterogeneous Fenton-like oxidation of acetic acid, which is one of the most resistant carboxylic acids to oxidation. For this purpose, firstly, the degradation of acetic acid was examined by using ultrasound alone and the effects of different parameters such as: type of sonication system, ultrasonic power, and addition of H2O2 were investigated on the degradation of acetic acid. There was no chemical oxygen demand (COD) reduction in the presence of sonication alone. In the presence of the heterogeneous Fenton-like oxidation process alone, at 303 K, COD reduction reached only 7.1% after 2 h of reaction. However, the combination of the heterogeneous Fenton-like oxidation process with ultrasound increased the COD reduction from 7.1% to 25.5% after 2 h of reaction in an ultrasonic bath operated at 40 kHz, while the COD reduction only increased from 7.1% to 8.9% in the ultrasonic reactor operated at 850 kHz. This result indicates that the hybrid process of ultrasound and heterogeneous Fenton-like oxidation is a promising process to degrade acetic acid.


Place Matters: Closing the Gap on Rural Primary Care Quality Improvement Capacity-the Healthy Hearts Northwest Study.
To compare rural independent and health system primary care practices with urban practices to external practice facilitation support in terms of recruitment, readiness, engagement, retention, and change in quality improvement (QI) capacity and quality metric performance. The setting consisted of 135 small or medium-sized primary care practices participating in the Healthy Hearts Northwest quality improvement initiative. The practices were stratified by geography, rural or urban, and by ownership (independent [physician-owned] or system-owned [health/hospital system]). The quality improvement capacity assessment (QICA) survey tool was used to measure QI at baseline and after 12 months of practice facilitation. Changes in 3 clinical quality measures (CQMs)-appropriate aspirin use, blood pressure (BP) control, and tobacco use screening and cessation-were measured at baseline in 2015 and follow-up in 2017. Rural practices were more likely to enroll in the study, with 1 out of 3.5 rural recruited practices enrolled, compared with 1 out of 7 urban practices enrolled. Rural independent practices had the lowest QI capacity at baseline, making the largest gain in establishing a regular QI process involving cross-functional teams. Rural independent practices made the greatest improvement in meeting the BP control CQM, from 55.5% to 66.1% (P ≤ .001) and the smoking cessation metric, from 72.3% to 86.7% (P ≤ .001). Investing practice facilitation and sustained QI strategies in rural independent practices, where the need is high and resources are low, will yield benefits that outweigh centrally prescribed models.


Radiotherapy (2500 rad) for testicular leukemia: local control and subsequent clinical events: a Southwest Oncology Group study.
The effectiveness of radiotherapy, 2500 rad over two weeks, in treating leukemic infiltrates of the testicles was studied in 38 boys who met the requirements for tissue conformation of testicular involvement and examination of the bone marrow. The study group was heterogeneous with respect to specific histology and prior therapy. Complete regression of testicular infiltrates was confirmed by repeated biopsy examinations of 32 of 33 patients undergoing the procedure. The single treatment failure occurred in a boy with acute myelogenous leukemia. In all other patients, local disease control following radiotherapy persisted throuthout the remainder of the clinical course. Three of 5 children, however, showed evidence of reseeding of the testicle as a part of the relapse process at post-mortem examination. Statistical analysis of data from the 35 patients with acute lymphocytic leukemia showed the subsequent course of the disease with respect to next relapse, involving either bone marrow (BM) or the central nervous system (CNS), to be dependent on the acute leukemia prognostic group, as determined by age and peripheral white blood cell count (WBC) at the time of diagnosis, and timing of extramedullary disease (EMD). Patients with poor prognosis at the time of diagnosis and EMD afterward had a 3.8 times greater risk of a subsequent BM or CNS relapse than did patients with good or average prognosis and no EMD at any time (P = 0.07). Of the candidate prognostic factors examined with repect to survival, only the number of prior BM relapses was of statistical significance (P = 0.044). Children with two or more prior BM relapses had the worst prognosis for survival from testicular relapse, with a death risk of 3.6 times greater per unit of time than that of children with no or one prior BM relapse. Protective BM and CNS rescue therapy was recommended for those otherwise in complete remission (CR) at the time of testicular relapse. The median times to next relapse for patients receiving both BM and CNS recue therapy and for patients given CNS recue only were 42+ and seven weeks, respectively ( P = 0.09). The type of rescue received did not appear to affect survival time following testicular CR.


The relationship between defibrillation threshold and total mortality.
The relationship between the defibrillation threshold (DFT) and total mortality is unclear. A university hospital prospectively maintained implantable defibrillator (ICD) database identified 508 patients who underwent ICD implantation and had DFT testing performed at implant. Patients were placed in one of three groups based on the implant DFT (high (≥20 J), moderate (19-11 J), or low DFT (≤10 J)). Sixty-seven patients had a high DFT, 216 had a moderate DFT, and 225 had a low DFT. The mean left ventricular ejection fraction (LVEF) was 0.25, 0.28, and 0.30 in the high, moderate, and low DFT groups, respectively, (p = 0.04). There were significantly more patients with a subcutaneous electrode in the high DFT group (p < 0.001), more patients taking amiodarone (p < 0.001), and more patients on oral anticoagulation (p = 0.04). There were a total of 140 deaths during the follow-up period (mean 3.2 ± 1.7 years). There were 24 deaths in the high DFT group (35.8%), 62 in the moderate DFT group (28.7%), and 54 in the low DFT group (24.0%) (p = 0.05). Implant DFT was a significant predictor of mortality (p = 0.01), as was age, LVEF (p < 0.001), CAD (p = 0.01), amiodarone use (p = 0.02), and hematoma at implant (p = 0.01). An elevated DFT was an independent predictor of mortality after controlling for all significant univariate variables (p = 0.004). A high-implant DFT predicts an adverse prognosis, even when an adequate ICD safety margin is present.


TrackMate 7: integrating state-of-the-art segmentation algorithms into tracking pipelines.
TrackMate is an automated tracking software used to analyze bioimages and is distributed as a Fiji plugin. Here, we introduce a new version of TrackMate. TrackMate 7 is built to address the broad spectrum of modern challenges researchers face by integrating state-of-the-art segmentation algorithms into tracking pipelines. We illustrate qualitatively and quantitatively that these new capabilities function effectively across a wide range of bio-imaging experiments.


Does gill boundary layer carbonic anhydrase contribute to carbon dioxide excretion: a comparison between dogfish (Squalus acanthias) and rainbow trout (Oncorhynchus mykiss).
In vivo experiments were conducted on spiny dogfish (Squalus acanthias) and rainbow trout (Oncorhynchus mykiss) in sea water to determine the potential role of externally oriented or gill boundary layer carbonic anhydrase in carbon dioxide excretion. This was accomplished by assessing pH changes in expired water using a stopped-flow apparatus. In dogfish, expired water was in acid-base disequilibrium as indicated by a pronounced acidification (delta pH=-0.11+/-0.01; N=22; mean +/- s.e.m.) during the period of stopped flow; inspired water, however, was in acid-base equilibrium (delta pH=-0.002+/-0.01; N=22). The acid-base disequilibrium in expired water was abolished (delta pH=-0.005+/-0.01; N=6) by the addition of bovine carbonic anhydrase (5 mg l-1) to the external medium. Addition of the carbonic anhydrase inhibitor acetazolamide (1 mmol l-1) to the water significantly reduced the magnitude of the pH disequilibrium (from -0.133+/-0.03 to -0.063+/-0.02; N=4). However, after correcting for the increased buffering capacity of the water caused by acetazolamide, the acid-base disequilibrium during stopped flow was unaffected by this treatment (control delta [H+]=99.8+/-22.8 micromol l-1; acetazolamide delta [H+]=81.3+/-21.5 micromol l-1). In rainbow trout, expired water displayed an acid-base disequilibrium (delta pH=0.09+/-0.01; N=6) that also was abolished by the application of external carbonic anhydrase (delta pH=0.02+/-0.01). The origin of the expired water acid-base disequilibrium was investigated further in dogfish. Intravascular injection of acetazolamide (40 mg kg-1) to inhibit internal carbonic anhydrase activity non-specifically and thus CO2 excretion significantly diminished the extent of the expired water disequilibrium pH after 30 min (from -0.123+/-0.01 to -0.065+/-0.01; N=6). Selective inhibition of extracellular carbonic anhydrase activity using a low intravascular dose (1.3 mg kg-1) of the inhibitor benzolamide caused a significant reduction in the acid-base disequilibrium after 5 min (from -0.11+/-0.01 to -0.07+/-0. 01; N=14). These results demonstrate that the expired water acid-base disequilibrium originates, at least in part, from excretory CO2 and that extracellular carbonic anhydrase in dogfish may have a significant role in carbon dioxide excretion. However, externally oriented carbonic anhydrase (if present in dogfish) plays no role in catalysing the hydration of the excretory CO2 in water flowing over the gills and thus is unlikely to facilitate CO2 excretion.


Integrative genetic and immune cell analysis of plasma proteins in healthy donors identifies novel associations involving primary immune deficiency genes.
Blood plasma proteins play an important role in immune defense against pathogens, including cytokine signaling, the complement system, and the acute-phase response. Recent large-scale studies have reported genetic (i.e., protein quantitative trait loci, pQTLs) and non-genetic factors, such as age and sex, as major determinants to inter-individual variability in immune response variation. However, the contribution of blood-cell composition to plasma protein heterogeneity has not been fully characterized and may act as a mediating factor in association studies. Here, we evaluated plasma protein levels from 400 unrelated healthy individuals of western European ancestry, who were stratified by sex and two decades of life (20-29 and 60-69 years), from the Milieu Intérieur cohort. We quantified 229 proteins by Luminex in a clinically certified laboratory and their levels of variation were analyzed together with 5.2 million single-nucleotide polymorphisms. With respect to non-genetic variables, we included 254 lifestyle and biochemical factors, as well as counts of seven circulating immune cell populations measured by hemogram and standardized flow cytometry. Collectively, we found 152 significant associations involving 49 proteins and 20 non-genetic variables. Consistent with previous studies, age and sex showed a global, pervasive impact on plasma protein heterogeneity, while body mass index and other health status variables were among the non-genetic factors with the highest number of associations. After controlling for these covariates, we identified 100 and 12 pQTLs acting in cis and trans, respectively, collectively associated with 87 plasma proteins and including 19 novel genetic associations. Genetic factors explained the largest fraction of the variability of plasma protein levels, as compared to non-genetic factors. In addition, blood-cell fractions, including leukocytes, lymphocytes, monocytes, neutrophils, eosinophils, basophils, and platelets, had a larger contribution to inter-individual variability than age and sex and appeared as confounders of specific genetic associations. Finally, we identified new genetic associations with plasma protein levels of five monogenic Mendelian disease genes including two primary immunodeficiency genes (Ficolin-3 and FAS). Our study identified novel genetic and non-genetic factors associated to plasma protein levels which may inform health status and disease management.


Specific inhibitor of complement (C5)-derived chemotactic activity in systemic lupus erythematosus related antigenically to the Bb fragment of human factor B.
Serum and plasma from patients with active systemic lupus erythematosus contain a specific inhibitor of complement (C5)-derived chemotactic activity. We found that the inhibitor is antigenically related to the Bb fragment of complement factor B. Lupus plasma and purified inhibitor significantly reduced the chemotactic activity of zymosan-treated normal serum, an effect that was abolished by antibodies to factor B. Similar results were obtained when purified Bb was used. Neither purified inhibitor nor Bb inhibited the chemotactic activity of purified human C5a or C5a des Arg. As reported previously, the chemotactic activity of C5a des Arg was enhanced significantly by the addition of an anionic polypeptide (cochemotaxin) present in normal serum and plasma. Interestingly, both purified lupus inhibitor and Bb inhibited the chemotactic activity exhibited by mixtures of C5a des Arg and its cochemotaxin. This effect was due, most likely, to their ability to neutralize the enhancing effect of the cochemotaxin on the chemotactic activity of C5a des Arg. Immunoelectrophoresis and western blots revealed that the purified inhibitor reacted with anti-factor B and exhibited a similar charge and molecular weight as purified Bb.


First Report of Microcyclosporella mali Causing Sooty Blotch and Flyspeck Disease on Plum in Poland.
Sooty blotch and flyspeck (SBFS), a disease caused by a complex of fungi, results in substantial economic losses for commercial growers of scab-resistant apple (Malus × domestica Borkh.) cultivars in Poland. However, many species causing SBFS in Poland are unidentified and sources of inoculum are uncertain. In August 2009, signs of SBFS were noted on fruit of plum (Prunus domestica L., cvs. Sweet Common Prune and Oullins Golden Gage) in orchards near Mostki in central Poland. Colonies consisted of olive green-to-black mycelial mats with few sclerotium-like bodies; infections ranged in severity from scattered spots to nearly complete coverage of the fruit surface. Ten of these colonies were isolated on potato dextrose agar (PDA). After 10 days of incubation at 22°C, total DNA was extracted; amplification of the internal transcribed spacer (ITS) region of rDNA utilized primers ITS1 and ITS4 (1). Nucleotide sequences were analyzed by ClustalW and compared with sequences in GenBank using BLAST. Sequences showed 99 to 100% homology to Microcyclosporella mali (2), which was formerly assigned as Pseudocercosporella sp. (1). Sequences from five isolates were submitted to GenBank (Accession Nos. HM101275, HM101276, HM101277, HM101278, and HM101279). Morphological characteristics-conidiogenous cells integrated, sympodial and polyblastic; conidial scars nonthickened and inconspicuous; conidia hyaline, subcylindric, narrow, straight or very slightly curved, truncate at the base and obtuse at the apex, often catenulate in simple or branched chains, with one (commonly) to five septa (12.5 × 2.6 to 50.7 × 4.0 μm)-were consistent with descriptions of M. mali (2). To fulfill Koch's postulates, each of the 10 isolates was used to inoculate three healthy apple fruit (cv. Golden Delicious) that had been previously washed under tap water and disinfested with 70% ethanol. After fruit were swabbed with cotton plugs that had been saturated with a suspension of spores in sterile distilled water (SDW), inoculated fruit were placed on filter paper that had been moistened with SDW, then sealed in foil bags and incubated at 22°C. When bags were removed 5 weeks later, dark colonies had appeared on the fruit. Isolates obtained from these colonies were morphologically identical to those used for inoculation. Control (SDW-inoculated and noninoculated) fruit that were incubated in the same manner developed no colonies. To our knowledge, this is the first report of SBFS on plum caused by M. mali in Poland; it had previously been noted as part of the SBFS complex on apple in Germany and Slovenia (2) and on apple and plum in the United States (3). References: (1) J. C. Batzer et al. Mycologia 97:1268, 2005. (2) J. Frank et al. Persoonia 24:93, 2010. (3) J. Latinović et al. Plant Dis. 91:1685, 2007.


Salamanders and fish can regenerate lost structures--why can't we?
The recent introduction of in vivo lineage-tracing techniques using fluorescently labeled cells challenged the long-standing view that complete dedifferentiation is a major force driving vertebrate tissue regeneration. The report in BMC Developmental Biology by Juan Carlos Izpisúa Belmonte and colleagues adds a new twist to a rapidly evolving view of the origin of blastemal cells. As classic and recent experimental findings are considered together, a new perspective on vertebrate muscle regeneration is emerging.See research article http://www.biomedcentral.com/1471-213X/12/9.


Validation of the Korean Version of the Biological Rhythms Interview of Assessment in Neuropsychiatry.
The Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN) is a scale used to clinically evaluate disturbances in biological rhythm. In this study, we aimed to examine the reliability and validity of the Korean version of the BRIAN (K-BRIAN) in a Korean population. A total of 181 participants, including 141 outpatients with bipolar disorder (BD; type I, 62; type II, 79) and 40 controls, were recruited. Construct validity was tested by comparing the mean K-BRIAN scores of the BD patients and control subjects. Concurrent validity was tested by evaluating the association between the K-BRIAN and the Morningness-Eveningness Questionnaire (MEQ). The mean K-BRIAN scores of the control subjects and patients with BD differed significantly (p<0.001). Particularly, the mean K-BRIAN score was considerably lower among control subjects (mean±standard deviation=35.00±8.88) than among patients with BD type I (41.19±12.10) and type II (50.18±13.73). The Cronbach's alpha for the K-BRIAN was 0.914. The K-BRIAN was found to correlate with the MEQ (r=-0.45, p<0.001). The findings affirm that the K-BRIAN has good construct validity and internal consistency. This suggests that the K-BRIAN can be used to assess biological rhythms in the Korean population, especially for patients with mood disorder.


National and transnational belonging among Turkish and Moroccan older migrants in the Netherlands: protective against loneliness?
This research investigates how a sense of belonging functions as protective mechanism against loneliness. Inspired by the work of Berry (1980) on acculturation strategies (i.e. integration, assimilation, separation and marginalization), we distinguish migrants who feel a relatively strong or weak sense of belonging to larger society and those who feel a strong or weak belonging to the "own group." We expect that more national belonging contributes to less loneliness. We add a transnational perspective by arguing that feelings of belonging to the own group can take place in the country of settlement, but can also be transnational, i.e. a feeling of belonging to the country of origin. Transnational belonging can protect against loneliness, as it acknowledges the importance of place attachment. Using data from the Longitudinal Aging Study Amsterdam on older migrants aged 55-66, we employ latent class analysis and find five national belonging clusters, interpretable in terms of Berry's acculturation strategies. Further analyses reveal mixed evidence: some aspects of transnational belonging vary with belonging to the own group, but other aspects point to a third dimension of belonging. Regression analysis shows that those marginalized are loneliest and that a transnational sense of belonging contributes to more loneliness. We conclude that Berry's (1980) typology is useful for interpreting older migrants' national belonging and that a transnational sense of belonging is apparent among older migrants, but needs to be explored further.


[Professional competences, clinical management and diagnostic related groups in Chilean public hospitals].
To define a professional skills model for the creation of an information system to support clinical management based on diagnosis related groups (DRG) in Chilean public hospitals. Mixed methodology. Qualitative, descriptive research based on focused interviews, with a theoretical or intentional sample of four leading DRG experts from Chile, with content analysis. Quantitative research using the Delphi method on 18 managers in charge of the implementation of DRG units in Chile, with three rounds. The analysis of quantitative data was carried out by clusters. After five iterations, 78 skills were evaluated out of a total of 179 as "high", including knowledge of the team leader, professional training (preferably nurses), 15 attitudes and values, 17 skills and 12 specific skills related to the coding system. There is a tendency among professionals to require the maximum skills; a massive behavior was observed, with low discrimination and prioritization. To analyze the causes that make decision-making difficult and to prioritize the required skills is proposed to determine the necessary level for each skill, the gaps between skill offer and demand, and to design a system for evaluating the impact of the model on the development of the skills among the teams.


Electrocatalysis for the oxygen evolution reaction: recent development and future perspectives.
There is still an ongoing effort to search for sustainable, clean and highly efficient energy generation to satisfy the energy needs of modern society. Among various advanced technologies, electrocatalysis for the oxygen evolution reaction (OER) plays a key role and numerous new electrocatalysts have been developed to improve the efficiency of gas evolution. Along the way, enormous effort has been devoted to finding high-performance electrocatalysts, which has also stimulated the invention of new techniques to investigate the properties of materials or the fundamental mechanism of the OER. This accumulated knowledge not only establishes the foundation of the mechanism of the OER, but also points out the important criteria for a good electrocatalyst based on a variety of studies. Even though it may be difficult to include all cases, the aim of this review is to inspect the current progress and offer a comprehensive insight toward the OER. This review begins with examining the theoretical principles of electrode kinetics and some measurement criteria for achieving a fair evaluation among the catalysts. The second part of this review acquaints some materials for performing OER activity, in which the metal oxide materials build the basis of OER mechanism while non-oxide materials exhibit greatly promising performance toward overall water-splitting. Attention of this review is also paid to in situ approaches to electrocatalytic behavior during OER, and this information is crucial and can provide efficient strategies to design perfect electrocatalysts for OER. Finally, the OER mechanism from the perspective of both recent experimental and theoretical investigations is discussed, as well as probable strategies for improving OER performance with regards to future developments.


Activation of KV7 channels stimulates vasodilatation of human placental chorionic plate arteries.
Potassium (K(+)) channels are key regulators of vascular smooth muscle cell (VSMC) excitability. In systemic small arteries, Kv7 channel expression/activity has been noted and a role in vascular tone regulation demonstrated. We aimed to demonstrate functional Kv7 channels in human fetoplacental small arteries. Human placental chorionic plate arteries (CPAs) were obtained at term. CPA responses to Kv7 channel modulators was determined by wire myography. Presence of Kv7 channel mRNA (encoded by KCNQ1-5) and protein expression were assessed by RT-PCR and immunohistochemistry/immunofluorescence, respectively. Kv7 channel blockade with linopirdine increased CPA basal tone and AVP-induced contraction. Pre-contracted CPAs (AVP; 80 mM K(+) depolarization solution) exhibited significant relaxation to flupirtine, retigabine, the acrylamide (S)-1, and (S) BMS-204352, differential activators of Kv7.1 - Kv7.5 channels. All CPAs assessed expressed KCNQ1 and KCNQ3-5 mRNA; KCNQ2 was expressed only in a subset of CPAs. Kv7 protein expression was confirmed in intact CPAs and isolated VSMCs. Kv7 channels are present and active in fetoplacental vessels, contributing to vascular tone regulation in normal pregnancy. Targeting these channels may represent a therapeutic intervention in pregnancies complicated by increased vascular resistance.


A qualitative study: potential benefits and challenges of traditional healers in providing aspects of palliative care in rural South Africa.
This article draws on selected palliative care providers' views and experiences to reflect on the potential benefits and possible challenges of involving traditional healers in palliative care in rural areas of South Africa. There is increasing consensus that palliative care should be offered by a range of professional and non-professional healthcare givers. Including non-professionals such as traditional healers in a palliative care team may strengthen care provisioning as they have intimate knowledge of patients' local culture and spiritual beliefs. Employing the qualitative method of photo-elicitation, one-on-one discussions about the photographs taken by participants were conducted. The participants - 4 palliative care nurses and 17 home-based care workers - were purposively selected to provide in-depth information about their experiences as palliative caregivers in rural homes. Healthcare workers' experiences revealed that the patients they cared for valued traditional rituals connected to illness, dying, death and bereavement. Participants suggested that traditional healers should be included in palliative care training programs as they could offer appropriate psychological, cultural and spiritual care. A challenge identified by participants was the potential of traditional healers to foster a false sense of longevity in patients facing death. The importance of recognising the value of traditional practices in palliative care should not be underrated in rural South Africa. Traditional healers could enhance palliative care services as they have deep, insider knowledge of patients' spiritual needs and awareness of cultural practices relating to illness, death, dying and bereavement. Incorporating traditional healers into healthcare services where there are differences in the worldviews of healthcare providers and patients, and a sensitivity to mediate cultural differences between caregivers and patients, could have the benefit of providing appropriate care in rural spaces. Considering the influences of cultural and spiritual beliefs on the wellbeing of patients living in rural areas, the inclusion of traditional healers in a palliative care team is a sensible move. It is, nevertheless, important to note that unanticipated challenges may arise with respect to power differentials within the palliative care team and to beliefs that contradict medical prognosis.


The power of allele frequency comparisons to detect the footprint of selection in natural and experimental situations.
Recently, inter-population comparisons of allele frequencies to detect past selection haven gained popularity. Data from genome-wide scans are used to detect the number and position of genes that have responded to unknown selection pressures in natural populations, or known selection pressures in experimental lines. Yet, the limitations and possibilities of these methods have not been well studied. In this paper, the objectives were (1) to investigate the distance over which a signal of directional selection is detectable under various scenarios, and (2) to study the power of the method depending on the properties of the used markers, for both natural populations and experimental set-ups. A combination of recurrence equations and simulations was used. The results show that intermediate strength selection on new mutations can be detected with a marker spacing of about 0.5 cM in large natural populations, 200 to 400 generations after the divergence of subpopulations. In experimental situations, only strong selection will be detectable, while markers can be spaced a few cM apart. Adaptation from standing variation in the base population will be hard to detect, though some solutions are presented for experimental designs.


Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation.
A broad analysis of adrenal gland-derived 19-carbon (C19) steroids has not been reported. This is the first study that uses liquid chromatography-tandem mass spectrometry to quantify 9 C19 steroids (androgens and their precursors), estrone, and estradiol in the adrenal vein (AV) of women, before and after ACTH stimulation. The objective of this study was to define the adrenal androgen metabolome in women before and after ACTH infusion. This was a retrospective study. Seven women, aged 50.4 ± 5.4 years, with suspected diagnosis of an adrenal aldosterone-producing adenoma were included in the study. AV and iliac serum samples were collected before and after administration of ACTH (15 minutes). AV samples were analyzed using for concentrations of 9 unconjugated C19 steroids, estrone, and estradiol. Dehydroepiandrosterone sulfate (DHEA-S) was quantified by radioimmunoassay. AV levels of DHEA-S were the highest among the steroids measured. The most abundant unconjugated C19 steroids in AV were 11β-hydroxyandrostenedione (11OHA), dehydroepiandrosterone (DHEA), and androstenedione (A4). ACTH significantly increased the adrenal output of 9 of the 12 steroids that were measured. ACTH increased the mean AV concentration of DHEA-S by 5-fold, DHEA by 21-fold, A4 by 7-fold, and 11OHA by 5-fold. 11β-Hydroxytestosterone and testosterone were found to be potent androgen receptor agonists when tested with an androgen-responsive cell reporter model. The current study indicates that the adrenal gland secretes primarily 3 weak androgens, namely DHEA, 11OHA, and A4. Active androgens, including testosterone and 11β-hydroxytestosterone, are also produced but to a lesser degree.


A novel microRNA-1207-3p/FNDC1/FN1/AR regulatory pathway in prostate cancer.
Prostate cancer (PCa) is the second most common cause of cancer-specific deaths in the U.S. Unfortunately, the underlying molecular mechanisms for its development and progression remain unclear. Studies have established that microRNAs (miRNAs) are dysregulated in PCa. The intron-derived microRNA-1207-3p (miR-1207-3p) is encoded at the non-protein coding gene locus PVT1 on the 8q24 human chromosomal region, an established PCa susceptibility locus. However, miR-1207-3p in PCa had not previously been investigated. Therefore, we explored if miR-1207-3p plays any regulatory role in PCa. We discovered that miR-1207-3p is significantly underexpressed in PCa cell lines in comparison to normal prostate epithelial cells, and that increased expression of microRNA-1207-3p in PCa cells significantly inhibits proliferation, migration, and induces apoptosis via direct molecular targeting of fibronectin type III domain containing 1 (FNDC1). Our studies also revealed significant overexpression of FNDC1, fibronectin (FN1) and the androgen receptor (AR) in human PCa cell lines as well as tissues, and FNDC1, FN1, and AR positively correlate with aggressive PCa. These findings, recently published in Experimental Cell Research, are the first to describe a novel miR-1207-3p/FNDC1/FN1/AR novel regulatory pathway in PCa.


End-user preferences for and performance of competing POU water treatment technologies among the rural poor of Kenya.
Household point-of-use (POU) water treatment technologies targeted at vulnerable populations are microbiologically effective and, in small trials, improve health. We do not understand the factors that influence preference for and adoption of these technologies by target end-users. We cycled 400 rural subsistence farm households in western Kenya through three randomly ordered two-month trials of three POU products: dilute hypochlorite solution, porous ceramic filtration, and a combined flocculant-disinfectant powdered mixture to compare relative end-user preferences and usage. Households reported higher usage of both dilute hypochlorite and filters than the flocculant-disinfectant. Averaged among all participating households, Escherichia coli reductions in treated water were generally higher among those that received dilute hypochlorite solution than among those receiving either of the other two products. Among those households that self-reported product usage, the E. coli reductions achieved by dilute hypochlorite and the flocculant-disinfectant are statistically equivalent to one another and higher than the reductions achieved by filters. At the same time, households ranked filters most frequently as their most preferred product.


Trends in the psychosocial characteristics of 11-15-year-olds who still drink, smoke, take drugs and engage in poly-substance use in England.
Youth substance use is declining in many high-income countries. As adolescent substance use becomes less common, it may concentrate in higher-risk groups. This paper aims to examine how the psychosocial characteristics of young substance users in England have changed over time. Annual cross-sectional data from the 2001-2014 Smoking, Drinking and Drug Use Among Young People in England survey are analysed (n = 112 792, age: 11-15). Logistic and Poisson regression analyses are used to test whether the sex, socioeconomic status (SES) and prevalence of truancy and exclusion from school of those who drink alcohol, smoke cigarettes, take cannabis, take other drugs and engage in poly-substance use changed across the study period. Use of all substances decreased and there were shifts in the psychosocial characteristics of young smokers, illicit drug users and poly-substance users. The proportion of current smokers and ever-users of cannabis of low SES and who had been excluded increased significantly between 2001/2003-2014. The proportion of last month drug users who had been excluded from school also increased significantly and there were increases in the proportion of polysubstance-users who had truanted and been excluded. The proportion of low SES alcohol users who had been excluded also increased significantly, but this change was very small. There was no evidence of substance use becoming more or less concentrated in one gender. There is some evidence that smoking, illicit drug use and poly-substance use are becoming more concentrated in potentially at risk populations. There is limited evidence of concentration amongst young drinkers.


Physician-reported barriers to using evidence-based recommendations for low back pain in clinical practice: a systematic review and synthesis of qualitative studies using the Theoretical Domains Framework.
Adoption of low back pain guidelines is a well-documented problem. Information to guide the development of behaviour change interventions is needed. The review is the first to synthesise the evidence regarding physicians' barriers to providing evidence-based care for LBP using the Theoretical Domains Framework (TDF). Using the TDF allowed us to map specific physician-reported barriers to individual guideline recommendations. Therefore, the results can provide direction to future interventions to increase physician compliance with evidence-based care for LBP. We searched the literature for qualitative studies from inception to July 2018. Two authors independently screened titles, abstracts, and full texts for eligibility and extracted data on study characteristics, reporting quality, and methodological rigour. Guided by a TDF coding manual, two reviewers independently coded the individual study themes using NVivo. After coding, we assessed confidence in the findings using the GRADE-CERQual approach. Fourteen studies (n = 318 physicians) from 9 countries reported barriers to adopting one of the 5 guideline-recommended behaviours regarding in-clinic diagnostic assessments (9 studies, n = 198), advice on activity (7 studies, n = 194), medication prescription (2 studies, n = 39), imaging referrals (11 studies, n = 270), and treatment/specialist referrals (8 studies, n = 193). Imaging behaviour is influenced by (1) social influence-from patients requesting an image or wanting a diagnosis (n = 252, 9 studies), (2) beliefs about consequence-physicians believe that providing a scan will reassure patients (n = 175, 6 studies), and (3) environmental context and resources-physicians report a lack of time to have a conversation with patients about diagnosis and why a scan is not needed (n = 179, 6 studies). Referrals to conservative care is influenced by environmental context and resources-long wait-times or a complete lack of access to adjunct services prevented physicians from referring to these services (n = 82, 5 studies). Physicians face numerous barriers to providing evidence-based LBP care which we have mapped onto 7 TDF domains. Two to five TDF domains are involved in determining physician behaviour, confirming the complexity of this problem. This is important as interventions often target a single domain where multiple domains are involved. Interventions designed to address all the domains involved while considering context-specific factors may prove most successful in increasing guideline adoption. PROSPERO 2017, CRD42017070703.


Evidence for weak or linear conformity but not for hyper-conformity in an everyday social learning context.
Conformity is thought to be an important force in cultural evolution because it has the potential to stabilize cooperation in large groups, potentiate group selection and thus explain uniquely human behaviors. However, the effects of such conformity on cultural and biological evolution will depend much on the way individuals are influenced by the frequency of alternative behavioral options witnessed. Theoretical modeling has suggested that only what we refer to as 'hyper-conformity', an exaggerated tendency to perform the most frequent behavior witnessed in other individuals, is able to increase within-group homogeneity and between-group diversity, for instance. Empirically however, few experiments have addressed how the frequency of behavior witnessed affects behavior. Accordingly we performed an experiment to test for the presence of conformity in a natural situation with humans. Visitors to a Zoo exhibit were invited to write or draw answers to questions on A5 cards and potentially win a small prize. We manipulated the proportion of existing writings versus drawings visible to visitors and measured the proportion of written cards submitted. We found a strong and significant effect of the proportion of text displayed on the proportion of text in the answers, thus demonstrating social learning. We show that this effect is approximately linear, with potentially a small, weak-conformist component but no hyper-conformist one. The present experiment therefore provides evidence for linear conformity in humans in a very natural context.


Chronic peripheral administration of corticotropin-releasing factor causes colonic barrier dysfunction similar to psychological stress.
Chronic psychological stress causes intestinal barrier dysfunction and impairs host defense mechanisms mediated by corticotrophin-releasing factor (CRF) and mast cells; however, the exact pathways involved are unclear. Here we investigated the effect of chronic CRF administration on colonic permeability and ion transport functions in rats and the role of mast cells in maintaining the abnormalities. CRF was delivered over 12 days via osmotic minipumps implanted subcutaneously in wild-type (+/+) and mast cell-deficient (Ws/Ws) rats. Colonic segments were excised for ex vivo functional studies in Ussing chambers [short-circuit current (Isc), conductance (G), and macromolecular permeability (horseradish peroxidase flux)], and analysis of morphological changes (mast cell numbers and bacterial host-interactions) was determined by light and electron microscopy. Chronic CRF treatment resulted in colonic mucosal dysfunction with increased Isc, G, and horseradish peroxidase flux in+/+but not in Ws/Ws rats. Furthermore, CRF administration caused mast cell hyperplasia and abnormal bacterial attachment and/or penetration into the mucosa only in+/+rats. Finally, selective CRF agonist/antagonist studies revealed that stimulation of CRF-R1 and CRF-R2 receptors induced the elevated secretory state and permeability dysfunction, respectively. Chronic CRF causes colonic barrier dysfunction in rats, which is mediated, at least in part, via mast cells. This information may be useful in designing novel treatment strategies for stress-related gastrointestinal disorders.


miRNA cargo within exosome-like vesicle transfer influences metastatic bone colonization.
Bone metastasis represents one of the most deleterious clinical consequences arising in the context of many solid tumors. Severe osteolysis results from tumor cell colonization of the bone compartment, a process which entails reciprocal exchange of soluble signals between tumor cells and their osseous microenvironment. Recent evidence indicates that tumor-intrinsic miRNAs are pleiotropic regulators of gene expression. But they are also frequently released in exosome-like vesicles (ELV). Yet the functional relevance of the transference of tumor-derived ELV and their miRNA cargo to the extracellular milieu during osseous colonization is unknown. Comparative transcriptomic profiling using an in vivo murine model of bone metastasis identified a repressed miRNA signature associated with high prometastatic activity. Forced expression of single miRNAs identified miR-192 that markedly appeased osseous metastasis in vivo, as shown by X-ray, bioluminescence imaging and microCT scans. Histological examination of metastatic lesions revealed impaired tumor-induced angiogenesis in vivo, an effect that was associated in vitro with decreased hallmarks of angiogenesis. Isolation and characterization of ELV by flow cytometry, Western blot analysis, transmission electron microscopy and nanoparticle tracking analysis revealed the ELV cargo enrichment in miR-192. Consistent with these findings, fluorescent labeled miR-192-enriched-ELV showed the in vitro transfer and release of miR-192 in target endothelial cells and abrogation of the angiogenic program by repression of proangiogenic IL-8, ICAM and CXCL1. Moreover, in vivo infusion of fluorescent labeled ELV efficiently targeted cells of the osseous compartment. Furthermore, treatment with miR-192 enriched ELV in a model of in vivo bone metastasis pre-conditioned osseous milieu and impaired tumor-induced angiogenesis, thereby reducing the metastatic burden and tumor colonization. Changes in the miRNA-cargo content within ELV represent a novel mechanism heavily influencing bone metastatic colonization, which is most likely relevant in other target organs. Mechanistic mimicry of this phenomenon by synthetic nanoparticles could eventually emerge as a novel therapeutic approach.


Postinfarction ventricular septal defect: an argument for early operation.
We reviewed our experience with 43 consecutive patients who underwent operations for postinfarction ventricular septal defect to determine optimal time for operative intervention, to identify factors responsible for failure of operative treatment, and to determine long-term survival rates. Patients were referred for operation after expectant medical management had failed or after 6 weeks electively. The operative mortality rate was 42% and ranged from 90% for those who required operation within 1 day of 11% for those underwent surgery after 1 month. In a multivariate discriminant analysis of preoperative variables, we found that inferior infarction with perforation (P less than 0.02) and preoperative multisystem failure (evidenced by abnormal mental status, P less than 0.02) were the major factors correlating with high operative risk. Early operation per se did not affect operative mortality rates. Technical problems with early operation were not a source of major morbidity and mortality. Actuarial long-term survival was good, and 88.5% of survivors were alive 5 years after surgery. Because preoperative multisystem failure is often progressive, we recommend immediate operation for all patients with postinfarction ventricular septal defect unless no deterioration is present. Moreover, because of the high risk of those patients with inferior infarction and perforation, we recommended immediate surgery for this group regardless of symptomatic status.


17HSD 2 may be higher in African-American breast cancer and is associated with estrogen receptor-negative tumors.
African-American women develop more aggressive breast cancers and at an earlier age compared with Caucasian women. We compared gene expression profiles of breast cancer cell lines that were developed from African-American and Caucasian patients to identify biological differences in breast cancers that develop in these groups. Real-time PCR was used to evaluate mRNA expression in cell lines and in a series of breast cancer cases. Gene microarray signal intensities were also analyzed in the International Genomics Consortium Expression Project for Oncology (expO) dataset. 17,-Hydroxysteroid dehydrogenase type 2 (17HSD 2) gene and mRNA expression were significantly higher in the African-American cell lines (p<0.05). However, 17HSD 2 expression did not differ significantly between the two cohorts in either our clinical series or the expO dataset. 17HSD 2 expression was found to be predictive of younger age at diagnosis and estrogen receptor status. Overexpression of 17HSD 2 in African-American breast cancer may contribute to the increased proportion of estrogen receptor-negative breast cancers and worse clinical outcome among African-American patients.


Homeopathic prescribing for chronic conditions in equine veterinary practice in the UK.
Twelve Faculty of Homeopathy veterinarians recorded data systematically at 777 consecutive homeopathic appointments for horses over a period of 12 months. A spreadsheet enabled the recording of information, which included the date of appointment; horse and owner identity (anonymised); sex of horse; main medical problem treated; whether the condition was chronic or acute; whether the appointment was new or a follow-up; owner-assessed clinical outcome on a seven-point scale, ranging from -3 to +3, compared with the first appointment; homeopathic medicine(s) prescribed; and whether any conventional or other complementary/alternative medicine (CAM) was being used concurrently to treat the condition. Data from 289 horses comprised a total of 305 individual conditions identified as chronic in nature, of which 234 had a follow-up assessment. At the final appointment for chronic cases during the study period, 4.3 per cent were receiving conventional medication and 17.1 per cent were being given another CAM treatment in addition to homeopathy. The eight chronic conditions most frequently treated with homeopathy were: arthritis, headshaking, laminitis, chronic obstructive pulmonary disease, sweet itch, dermatitis, sarcoidosis and Cushing's syndrome.


Combined effects of whey protein hydrolysates and probiotics on oxidative stress induced by an iron-overloaded diet in rats.
Whey proteins possess antioxidant properties, and probiotics have various health-promoting effects. We investigated the effects of whey protein hydrolysates (WPHs) and probiotics in rats exposed to oxidative stress induced by iron-overload diet (IOL). Rats were divided into control (CTRL), IOL (0.2% ferrous sulphate), WPH (10%), probiotic (PB) mixture (Lactococcus lactis NK34 and B. polyfermenticus SCD), and WPH + PB group for 6 weeks. Average leukocytes and colonocytes tail moments were increased in IOL compared to CTRL but decreased in other groups. Conjugated diene was lower in WPH, PB, and WPH + PB than in IOL. Only WPH + PB group could recover glutathione S-transferase (GST) levels. SOD levels were recovered by WPH and PB. PB and WPH + PB increased α-tocopherol and only WPH + PB increased γ-tocopherol. Thus, our data demonstrated that WPH and PB exhibit antioxidant properties in a rat model of high-iron diet-induced oxidative stress and combination of them may provide an enhanced effect.


Direct evidence of Neanderthal fibre technology and its cognitive and behavioral implications.
Neanderthals are often considered as less technologically advanced than modern humans. However, we typically only find faunal remains or stone tools at Paleolithic sites. Perishable materials, comprising the vast majority of material culture items, are typically missing. Individual twisted fibres on stone tools from the Abri du Maras led to the hypothesis of Neanderthal string production in the past, but conclusive evidence was lacking. Here we show direct evidence of fibre technology in the form of a 3-ply cord fragment made from inner bark fibres on a stone tool recovered in situ from the same site. Twisted fibres provide the basis for clothing, rope, bags, nets, mats, boats, etc. which, once discovered, would have become an indispensable part of daily life. Understanding and use of twisted fibres implies the use of complex multi-component technology as well as a mathematical understanding of pairs, sets, and numbers. Added to recent evidence of birch bark tar, art, and shell beads, the idea that Neanderthals were cognitively inferior to modern humans is becoming increasingly untenable.


Construction of a DOPC/PSM/cholesterol phase diagram based on the fluorescence properties of trans-parinaric acid.
Cell membranes have a nonhomogenous lateral organization. Most information about such nonhomogenous mixing has been obtained from model membrane studies where defined lipid mixtures have been characterized. Various experimental approaches have been used to determine binary and ternary phase diagrams for systems under equilibrium conditions. Such phase diagrams are the most useful tools for understanding the lateral organization in cellular membranes. Here we have used the fluorescence properties of trans-parinaric acid (tPA) for phase diagram determination. The fluorescence intensity, anisotropy, and fluorescence lifetimes of tPA were measured in bilayers composed of one to three lipid components. All of these parameters could be used to determine the presence of liquid-ordered and gel phases in the samples. However, the clearest information about the phase state of the lipid bilayers was obtained from the fluorescence lifetimes of tPA. This is due to the fact that an intermediate-length lifetime was found in samples that contain a liquid-ordered phase and a long lifetime was found in samples that contained a gel phase, whereas tPA in the liquid-disordered phase has a markedly shorter fluorescence lifetime. On the basis of the measured fluorescence parameters, a phase diagram for the 1,2-dioleoyl-sn-glycero-3-phosphocholine/N-palmitoyl sphingomyelin/cholesterol system at 23 °C was prepared with a 5 mol % resolution. We conclude that tPA is a good fluorophore for probing the phase behavior of complex lipid mixtures, especially because multilamellar vesicles can be used. The determined phase diagram shows a clear resemblance to the microscopically determined phase diagram for the same system. However, there are also significant differences that likely are due to tPA's sensitivity to the presence of submicroscopic liquid-ordered and gel phase domains.


Determination of Betaines by Fast Atom Bombardment Mass Spectrometry : Identification of Glycine Betaine Deficient Genotypes of Zea mays.
A rapid, sensitive, and selective method for the determination of betaines is described and discussed. The method entails derivatizing the quaternary ammonium compounds to increase their sensitivity to detection by fast atom bombardment mass spectrometry. Sensitivity of detection increases markedly as the length of the carbon chain of the alcohol used to esterify the betaine carboxylic acid group is increased (C4 > C3 > C2 > C1 > C0). The lower limit of detection of glycine betaine as the n-propyl ester is 0.05 nanomole per microliter of glycerol. Betaine aldehyde can be readily derivatized to the di-n-butyl or di-n-propyl acetal derivatives which exhibit lower limits of detection of about 5 picomoles and 10 picomoles per microliter of glycerol, respectively. Accurate quantification of these compounds is accomplished by the use of deuterium labeled internal standards or quaternary ammonium compound homologs of distinct mass. Methods for the synthesis of these internal standards are reported. Some applications of these methods are illustrated with stable isotope tracer studies on the kinetics of metabolism of choline to betaine aldehyde and glycine betaine in spinach leaf discs, and the identification of several Zea mays genotypes which appear deficient in glycine betaine. Tracer studies with deuterium labeled betaine aldehyde suggest that the deficiency of glycine betaine in one sweet corn hybrid is probably not due to a deficiency in the capacity to oxidize betaine aldehyde.


KetoCalculator: a web-based calculator for the ketogenic diet.
The classic ketogenic diet (KD) is a mathematically calculated diet with specific daily goals of fat, protein, and carbohydrate. Precise quantities of foods are then derived from these values which result in meal plans for the individual patient. The algebraic algorithm to determine a single meal requires approximately 35 calculations. This process is time consuming given that each individual requires many meals for variety and satisfaction. Computer applications can process multiple calculations in seconds. In 1997, a program was designed by this author with LifeTime Computing, a computer software company. This program was rebuilt into digital format in 2002, given the title KetoCalculator, and made available to registered dietitians on the World Wide Web (Zupec-Kania, 2002).


Motivation deficit in ADHD is associated with dysfunction of the dopamine reward pathway.
Attention-deficit hyperactivity disorder (ADHD) is typically characterized as a disorder of inattention and hyperactivity/impulsivity but there is increasing evidence of deficits in motivation. Using positron emission tomography (PET), we showed decreased function in the brain dopamine reward pathway in adults with ADHD, which, we hypothesized, could underlie the motivation deficits in this disorder. To evaluate this hypothesis, we performed secondary analyses to assess the correlation between the PET measures of dopamine D2/D3 receptor and dopamine transporter availability (obtained with [(11)C]raclopride and [(11)C]cocaine, respectively) in the dopamine reward pathway (midbrain and nucleus accumbens) and a surrogate measure of trait motivation (assessed using the Achievement scale on the Multidimensional Personality Questionnaire or MPQ) in 45 ADHD participants and 41 controls. The Achievement scale was lower in ADHD participants than in controls (11±5 vs 14±3, P<0.001) and was significantly correlated with D2/D3 receptors (accumbens: r=0.39, P<0.008; midbrain: r=0.41, P<0.005) and transporters (accumbens: r=0.35, P<0.02) in ADHD participants, but not in controls. ADHD participants also had lower values in the Constraint factor and higher values in the Negative Emotionality factor of the MPQ but did not differ in the Positive Emotionality factor-and none of these were correlated with the dopamine measures. In ADHD participants, scores in the Achievement scale were also negatively correlated with symptoms of inattention (CAARS A, E and SWAN I). These findings provide evidence that disruption of the dopamine reward pathway is associated with motivation deficits in ADHD adults, which may contribute to attention deficits and supports the use of therapeutic interventions to enhance motivation in ADHD.


Agricultural intensification escalates future conservation costs.
The supposition that agricultural intensification results in land sparing for conservation has become central to policy formulations across the tropics. However, underlying assumptions remain uncertain and have been little explored in the context of conservation incentive schemes such as policies for Reducing Emissions from Deforestation and forest Degradation, conservation, sustainable management, and enhancement of carbon stocks (REDD+). Incipient REDD+ forest carbon policies in a number of countries propose agricultural intensification measures to replace extensive "slash-and-burn" farming systems. These may result in conservation in some contexts, but will also increase future agricultural land rents as productivity increases, creating new incentives for agricultural expansion and deforestation. While robust governance can help to ensure land sparing, we propose that conservation incentives will also have to increase over time, tracking future agricultural land rents, which might lead to runaway conservation costs. We present a conceptual framework that depicts these relationships, supported by an illustrative model of the intensification of key crops in the Democratic Republic of Congo, a leading REDD+ country. A von Thünen land rent model is combined with geographic information systems mapping to demonstrate how agricultural intensification could influence future conservation costs. Once postintensification agricultural land rents are considered, the cost of reducing forest sector emissions could significantly exceed current and projected carbon credit prices. Our analysis highlights the importance of considering escalating conservation costs from agricultural intensification when designing conservation initiatives.


Systematic Investigation of Benzodithiophene-Benzothiadiazole Isomers for Organic Photovoltaics.
Two new donor-acceptor small molecules based on benzo[1,2-b:4,5-b']dithiophene (BDT) and benzo[c][1,2,5]thiadiazole (BT) were designed and synthesized. Small molecules 4,4'-[(4,8-bis(5-(2-ethylhexyl)thiophen-2-yl)benzo[1,2-b:4,5-b']dithiophene-2,6-diyl)bis(2,2'-bithiophene)-5,5'-diyl]bis(benzo[c][1,2,5]thiadiazole) (BDT-TT-BT) and 4,4'-(4,8-bis(5-(2-ethylhexyl)thiophen-2-yl)benzo[1,2-b:4,5-b']dithiophene-2,6-diyl)bis[7-(2,2'-bithiophene-5-yl)benzo[c][1,2,5]thiadiazole] (BDT-BT-TT) are structural isomers with the 2,2-bithiophene unit placed either between the BDT and BT units or at the end of the BT units. This work is targeted toward finding the effect of structural variation on optoelectronic properties, morphology, and photovoltaic performance. On the basis of theoretical calculations, the molecular geometry and energy levels are different for these two molecules when the position of the 2,2-bithiophene unit is changed. Optical and electrochemical properties of these two small molecules were characterized using UV-vis and cyclic voltammetry. The results showed that BDT-BT-TT has broader absorption and an elevated HOMO energy level when compared with those of BDT-TT-BT. The performance of these two isomers in solar cell devices was tested by blending with [6,6]-phenyl-C71-butyric acid methyl ester (PC71BM). Power conversion efficiencies as high as 3.22 and 3.71% were obtained in conventional solar cell structures for BDT-TT-BT and BDT-BT-TT, respectively. The morphology was studied using grazing incident wide-angle X-ray scattering and transmission electron microscopy, which revealed different phase separations of these two molecules when blended with PC71BM.


Highlights from the Third International Central Nervous System Germ Cell Tumour symposium: laying the foundations for future consensus.
The Third International Central Nervous System (CNS) Germ Cell Tumour (GCT) Symposium brought together over 100 delegates from all over the world to learn about the latest developments in these tumours and discuss future strategies for their management. Some areas of consensus were agreed upon, and controversies were discussed. Among these, the classification of GCTs and the surgical approach to their management were among the greatest areas of difference between different parts of the world. The need for radiotherapy (RT) as a part of standard first-line management for all malignant CNS GCTs was agreed, as well as the need for additional chemotherapy to maximise the cure in nongerminomatous malignant GCTs; the benefit of the addition of chemotherapy in localised germinoma to reduce the RT burden was also accepted as a good practice. The potential of biological parameters to assist the future diagnosis, treatment stratification, and disease monitoring for CNS GCTs was discussed. Such biological parameters may also represent targets for the development of novel therapies. The need for further collaboration between groups engaged in biological studies was agreed. The merits of proton beam RT were debated, and the importance of mitigating the long-term side effects of the treatment was underlined by a session on late effects.


Batteryless implantable device with built-in mechanical clock for automated and precisely timed drug administration.
Adherence to medication plays a crucial role in the effective management of chronic diseases. However, patients often miss their scheduled drug administrations, resulting in suboptimal disease control. Therefore, we propose an implantable device enabled with automated and precisely timed drug administration. Our device incorporates a built-in mechanical clock movement to utilize a clockwork mechanism, i.e., a periodic turn of the hour axis, enabling automatic drug infusion at precise 12-h intervals. The actuation principle relies on the sophisticated design of the device, where the rotational movement of the hour axis is converted into potential mechanical energy and is abruptly released at the exact moment for drug administration. The clock movement can be charged either automatically by mechanical agitations or manually by winding the crown, while the device remains implanted, thereby enabling the device to be used permanently without the need for batteries. When tested using metoprolol, an antihypertensive drug, in a spontaneously hypertensive animal model, the implanted device can deliver drug automatically at precise 12-h intervals without the need for further attention, leading to similarly effective blood pressure control and ultimately, prevention of ventricular hypertrophy as compared with scheduled drug administrations. These findings suggest that our device is a promising alternative to conventional methods for complex drug administration.


Fc receptor stimulation of phosphatidylinositol 3-kinase in natural killer cells is associated with protein kinase C-independent granule release and cell-mediated cytotoxicity.
Although diverse signaling events are initiated by stimulation of multichain immune recognition receptors on lymphocytes, it remains unclear as to which specific signal transduction pathways are functionally linked to granule exocytosis and cellular cytotoxicity. In the case of natural killer (NK) cells, it has been presumed that the rapid activation of protein kinase C (PKC) enables them to mediate antibody-dependent cellular cytotoxicity (ADCC) and "natural" cytotoxicity toward tumor cells. However, using cloned human NK cells, we determined here that Fc receptor stimulation triggers granule release and ADCC through a PKC-independent pathway. Specifically, pretreatment of NK cells with the selective PKC inhibitor, GF109203X (using concentrations that fully blocked phorbol myristate acetate/ionomycin-induced secretion) had no effect on FcR-initiated granule release or ADCC. In contrast, FcR ligation led to the rapid activation of phosphatidylinositol 3-kinase (PI 3-kinase), and inhibition of this enzyme with the selective inhibitor, wortmannin, blocked FcR-induced granule release and ADCC. Additional experiments showed that, whereas FcR-initiated killing was wortmannin sensitive and GF109203X insensitive, natural cytotoxic activity toward the tumor cell line K562 was wortmannin insensitive and GF109203X sensitive. Taken together, these results suggest that: (a) PI 3-kinase activation induced by FcR ligation is functionally coupled to granule exocytosis and ADCC; and (b) the signaling pathways involved in ADCC vs natural cytotoxicity are distinct.


Dopamine D4 receptor 48-bp repeat polymorphism: no association with response to antipsychotic treatment, but association with catatonic schizophrenia.
The dopamine D4 receptor (DRD4) may play a role in the pathogenesis of neuropsychiatric disease and in the action of dopaminergic drugs. The 48-bp repeat polymorphism (48-bp VNTR) coding for a 16-amino acid segment in the third cytoplasmatic loop of the DRD4 was studied as a predictor of the therapeutic response to antipsychotics and as susceptibility factor for schizophrenia. We included 638 in-patients with acute schizophrenic, schizoaffective (mainly schizophrenic), and other nonaffective psychoses, as well as two reference groups: one with 278 in-patients with non-psychiatric diseases, and one with 474 healthy volunteers. Catatonic patients (DSM-IV 295.2) more frequently carried the DRD4 D4.2 and D4.3 allele than did all other schizophrenic cases (P < 0.001; OR: 2.7; CI: 1.5-4.9) and controls (P < 0.004; OR: 2.3; CI: 1.3-4.2). We found no significant difference in the DRD4 allele or in genotype frequencies in our comparison of all schizophrenic patients and controls. The subgroups with affected family members, and the subgroups with early or late onset of disease, also did not differ from the controls in DRD4 allele frequencies. The 48-bp VNTR was not a predictor for therapeutic outcome measured by the positive and negative symptoms scale. A total of 1390 subjects showed between 1 and 10 repeats (D4. 1 and D4.10), with 25 different genotypes. These data exclude a major role of DRD4 48-bp VNTR in response to antipsychotic therapy and as susceptibility factor for schizophrenia, but catatonic schizophrenia may be associated with the D4.2 and D4.3 alleles.


The low-density-lipoprotein receptor-related protein (LRP) is processed by furin in vivo and in vitro.
The low-density-lipoprotein receptor-related protein (LRP) is a multifunctional receptor involved in the clearance of a large number of diverse ligands, including proteases, protease-inhibitor complexes and lipoproteins. The mature receptor is composed of a 515 kDa and a 85 kDa subunit generated by proteolytic cleavage from a 600 kDa precursor polypeptide in a trans-Golgi compartment. Proteolytic processing occurs C-terminal to the tetrabasic amino acid sequence RHRR, a consensus recognition site for precursor processing endoproteases or convertases. In this study we have identified furin, a subtilisin-type protease, to be necessary for efficient processing of LRP in cells. Furin-deficient RPE.40 cells exhibited an impaired processing of endogenous LRP and of a recombinant soluble form of the receptor containing the processing site. The processing defect in RPE.40 cells could be complemented by expression of furin from a transfected cDNA in cultured cells and by purified furin in vitro. The impaired maturation of LRP in RPE.40 cells did not affect its intracellular transport, and correlated with a slight but consistent reduction in the endocytosis of LRP-specific ligands. These data suggest that proteolytic processing of LRP by furin is not necessary for intracellular trafficking but might be required for normal receptor activity.


Effect of the spin-trapping compound N-tert-butyl-alpha-phenylnitrone on protein oxidation and life span.
N-tert-Butyl-alpha-phenylnitrone (PBN), a lipophilic spin-trapping compound, has been reported to decrease the concentration of protein carbonyls, the products of protein oxidation, in the brain of old gerbils to virtually the level found in the young gerbils (Carney, J. M., et al. (1991) Proc. Natl. Acad. Sci. USA 88, 3633-3636). The validity of this finding as well as that of the commonly used 2,4-dinitrophenylhydrazine procedure for the measurement of protein carbonyls was recently called into question by Cao and Cutler ((1995) Arch. Biochem. Biophys. 320, 106-114). The objective of the present study was to examine some of the relevant issues such as (a) whether the original findings on the effects of PBN can be confirmed, (b) whether similar effects of PBN occur in other species and tissues, and (c) whether PBN affects the life span of animals. Results of this study provide confirmation of the original finding that PBN indeed causes a decrease in protein carbonyl content in the gerbil brain cortex. However, a similar effect is not observed in the gerbil heart or the mouse brain cortex. Effects of PBN on protein carbonyls are thus variable depending upon tissue and species. PBN administration did not extend the life span of houseflies and at relatively high concentrations it was found to be toxic.


Computed tomography and radiographic indirect lymphography for visualization of mammary lymphatic vessels and the sentinel lymph node in normal cats.
The potential of computed tomography indirect lymphography (CT-indirect lymphography) and radiographic indirect lymphography to demonstrate the draining lymphatic vessels and sentinel lymph node of normal mammary glands was tested in 31 healthy female cats. The lymphatic drainage of each mammary gland was studied initially by CT-indirect lymphography after intramammary injection of 0.5 ml of iopamidol, followed by images acquired at 1, 5, 15, and 30 min after injection. One day after CT-indirect lymphography, the lymph drainage of the mammary gland was assessed using radiographic in direct lymphography af terintramammary injection of 0.5 ml of ethiodized oil followed by radiographs made at 1, 5, 15, 30, 45, and 60 min after injection. The time between intramammary injection and opacification of the draining mammary lymphatic vessels and the sentinel lymph node, the duration of adequate opacification of the draining mammary lymphatic vessels and of the sentinel lymph node and also the number and course of draining mammary lymphatic vessels and location of sentinel lymph node were compared for CT-indirect lymphography vs. radiographic indirect lymphography in each examined gland. This results suggest that radiographic indirect lymphography is easy to perform and can be used for accurate demonstration of the draining lymphatic pathways of mammary glands in radiographs made at 5-30 min after injection. However, CT-indirect lymphography was able to better demonstrate small lymphatic vessels and accurately define the exact topography of the sentinel lymph node in images acquired at 1 min after injection.


Allelic D variants of transferrin in evaluation of alcohol abuse: differential diagnosis by isoelectric focusing-immunoblotting-laser densitometry.
In the diagnosis of alcohol abuse transferrin (Tf) allelic D variants generate false-positive test results for carbohydrate-deficient transferrin (CDT) as assessed by their electrophoretic migration patterns. The predominant Tf C1 allele encodes a protein for which the most prevalent isoform has a pI of 5.4, i.e., four sialic acids and two bound ion molecules. Carriers of allele D encode Tfs with different amino acid sequences, for which the pI is > 5.7, despite their identical iron and carbohydrate composition. We used isoelectric focusing, immunoblotting, and laser densitometry (IEF-IB-LD) to distinguish Tf D variants from CDT. Alcohol abusers carrying the D chi allele tested CDT+; D chi nondrinkers were CDT-. Although normal controls (< 15 g of alcohol per day for 7-10 consecutive days) carrying variants D1, D2, or D chi exhibited abnormal IEF banding patterns, they did not generate false-positive results for CDT. D3 variants expressed isoforms that migrate at the same pI as CDT bands. Thus, IEF-IB-LD yields a highly resolved banding pattern to distinguish most Tf D variants from CDT.


Influence of the incorporation mode of sugar beet pulp in the finishing diet on the digestive tract and performances of geese reared for foie gras production.
The aim of this work was to study the effects of incorporating sugar beet pulp (SBP) into the diet of geese in two feeding systems (complete pelleted feed or loose-mix feeding system) on crop development and performance. A total of 480 1-d-old male geese were divided into three groups whose diet differed from d 56 to 90: a complete pelleted diet containing 50% corn (control diet: AMEn 11.5 MJ/kg; CP 161 g/kg), and no SBP; a complete pelleted diet containing 50% corn and 10% SBP (SBPcp diet: AMEn: 11.5 MJ/kg; CP: 161 g/kg); and a mix in the same feeder (SBPlm diet) of 500 g/kg of protein-rich pellets containing 20% SBP (SBPprp: AMEn: 9.0 MJ/kg; CP: 250 g/kg) and 500 g/kg of whole corn (WC: AMEn: 14.0 MJ/kg; CP: 72 g/kg). Body traits, including crop volume, were measured at d 91. From d 91 to 106, 88 birds/group were overfed with a mixture containing mainly corn and water before slaughter to measure fatty liver performance. Feed intake from d 56 to 90 was higher (+10%; P = 0.004) in the SBPcp group than the other two, but at d 90, the body weight (BW) of the birds was higher (+7%; P = 0.002) in the SBPlm group than the other two. At d 91, the volume of the crop was greater in the SBPcp group (80.4 mL/kg of BW, P < 0.001) than in the control group (60.3 mL/kg of BW), the SBPlm group being intermediate (64.1 mL/kg of BW). Feed intake (13,321 g), weight gain (2,733 g), and feed-to-gain ratio (4.9) during the overfeeding period, as well as fatty liver weight (963 g) and commercial grading, were similar (P > 0.05) between the three groups. In conclusion, the use of sugar beet pulp in the diet of finishing geese helps the adaptation of the digestive tract to the overfeeding period, even in a loose-mix feeding system based on whole corn.


Sildenafil (viagra) and the heart.
Sildenafil (Viagra) is the most effective oral therapy currently available for erectile dysfunction. Patients should be given clear instructions regarding the use of sildenafil. The most common side effects include flushing, headaches, dyspepsia, and transient visual changes. In combination with nitrates, it can and has caused fatal hypotension. It should not be prescribed to patients on nitrates. Additionally, nitrates should not be administered to anyone who has recently ingested sildenafil. Synergetic blood pressure lowering has not been observed when sildenafil was used with other classes of antihypertensives. Sildenafil is not offered to patients with low cardiac output states, those on intensive regimens to prevent heart failure or those with acute coronary ischemia.


Problems and pitfalls in the isolation of an endogenous Na+, K+-ATPase inhibitor.
Plasma from volume-expanded and salt-loaded hypertensive animals and from patients with essential hypertension has been reported to inhibit Na+, K+-adenosine triphosphatase (ATPase). Inhibition of the sodium pump in vascular smooth muscle caused by such a circulating factor could increase vascular tone and sensitivity to vasoactive agents, and thereby result in arterial hypertension. Numerous efforts in the past failed to isolate the putative factor from urine and plasma. Recent studies have suggested that the hypothalamus is an important source of an endogenous Na+, K+-ATPase inhibitor, but its isolation from the tissue extracts has been rendered difficult by the presence of other cellular constituents that cause artifactual interference with the assays and purification procedures. Using an alternative approach of isolating the inhibitor from culture medium, we found that dispersed fetal rat hypothalamic neurons in a capillary culture system release a heat-stable, peptidic, low-molecular-weight, active sodium transport inhibitor that causes a reversible increase in vascular tone, sensitizes vascular smooth muscle to the vasoactive effect of norepinephrine, and possesses several characteristics of the putative endogenous digitalislike factor. This inhibitor may be a chemical mediator linking kidney, brain, and cardiovascular system in the genesis of experimental volume-expanded and salt-loaded hypertension and human essential hypertension.