Fracture resistance of maxillary premolars with class II MOD cavities restored with Ormocer, Nanofilled, and Nanoceramic composite restorative systems.
To assess the influence of ormocer, nanofilled, nanoceramic, and microhybrid composite restorative systems on the fracture resistance of maxillary premolars with Class II mesio-occlusodistal (MOD) cavities. Eighty-four sound maxillary human premolars were divided into six groups of 14 teeth each. Teeth in the first group were left intact and tested as unprepared positive controls. Teeth in the remaining five groups were prepared with MOD cavities. Teeth in one of the five groups were unrestored and tested as negative control. The remaining four groups were restored with an ormocer (Admira), a nanofilled composite (Filtek Supreme), a nanoceramic composite (CeramX mono), and a microhybrid composite (Tetric Ceram). All groups were stored in water at 37°C for 24 hours and thermocycled 500 times between 5°C and 55°C. The specimens were loaded occlusally in a universal testing machine using a metal sphere that contacted only the teeth on the cuspal inclines until fracture occurred. The results were analyzed by Kruskal-Wallis and Mann-Whitney U tests. The level of significance was set at .05. The difference between the mean cuspal fracture resistance of the unprepared positive control teeth and those restored with ormocer, nanofill, and microhybrid composite was found to be statistically significant (P < .05). No statistically significant difference in cuspal fracture resistance was found between the unprepared positive control teeth and those teeth restored with nanoceramic composite (P > .05). Under compressive load testing, teeth with microhybrid, ormocer, and nanofilled composite restorations had lower cuspal fracture resistance than those with nanoceramic composite restorations.


Water, acidosis, and experimental pyelonephritis.
The effect of water restriction and ammonium chloride acidosis on the course of Escherichia coli pyelonephritis was determined in the nonobstructed kidney of the rat. To alter the chemical composition of the renal medulla, water intake was reduced in rats to one-half the normal daily intake. Water restriction increased the incidence of coliform pyelonephritis. Systemic acidosis, produced by giving a 300 mM solution of ammonium chloride, increased urinary osmolality to values comparable to water restriction and also predisposed to pyelonephritis. However, when rats were fed the same solution of ammonium chloride but were allowed access to tap water ad lib., urinary osmolality values were comparable to those observed in normal animals, and susceptibility to pyelonephritis was reduced or eliminated despite a degree of systemic acidosis similar to that observed in rats fed ammonium chloride solution without access to tap water. These results suggest that water diuresis may overcome the inactivation of complement produced by ammonium chloride acidosis and that renal medullary hypertonicity, produced by either water restriction or ammonium chloride acidosis, is a major determinant of this tissue's unique susceptibility to infection.


Radon-222 levels in New York State homes.
Results are presented from a statewide survey that measured annual 222Rn concentrations in over 2000 single-family, owner-occupied homes in New York state. The participants were selected by a random-digit-dialing telephone interview approach developed by Mitofsky-Waksberg which allows inferences to be made from the sample to the statewide population. After completing a telephone questionnaire and agreeing to have their homes monitored, eligible households were mailed alpha-track detectors with instructions to place one detector in the main living area for 2 mo (during the winter heating season), a second in the main living area for 1 y, and a third in the basement (if applicable) for 1 y. The statewide median concentration for the heating-season, living-area readings was 31.6 Bq m-3, with a median of 24.0 Bq m-3 for the annual living-area readings and 51.8 for the annual basement readings. For the state, approximately 95% of the living-area concentrations and 86% of the basement concentrations were below 148 Bq m-3 (4 pCi L-1). In addition, only 1.4% of the readings in the basement were above 740 Bq m-3 (20 pCi L-1).


Frailty and Neurodegenerative Disease: Anticipating the Future, Expanding the Framework.
An array of technologies for preventing and treating age-related neural decline and disease are currently under development. A clear framework for how to identify groups in need of such inventions is needed. An encompassing concept of frailty could provide a solid basis for such purposes. Concepts of frailty, including physical and cognitive frailty, are currently applied in clinical settings, and in research and development. The terminology facilitates identifying processes of age-related physical and cognitive decline. However, age-related neurodegenerative diseases do not fit the conceptual framework of frailty. A terminology of frailty can and should be developed that connects aging, cognitive decline, and neurodegenerative disease. Such a framework needs to (a) adequately account for the effects that the processes of aging have on neural decline and disease, and (b) be helpful in identifying relevant groups of users and patients.


Questionnaire investigation of musicians' use of hearing protectors, self reported hearing disorders, and their experience of their working environment.
Musicians in symphony orchestras are exposed to harmful sound levels. Although research shows that industrial workers have a higher propensity to noise-induced hearing loss, musicians can also develop a hearing loss from noise exposure. Furthermore, musicians can suffer from tinnitus, hyperacusis, and distortion, among other hearing disorders, which can affect their work more severely than a hearing loss. This study investigated the use of hearing protectors, the prevalence of self-reported hearing disorders among musicians, and the importance of these hearing disorders to the musicians. The musicians at three Danish symphony orchestras were asked to complete a questionnaire on the topic. Results showed that Danish musicians are aware of the dangers of loud music, yet they rarely use hearing protectors and not always correctly; however, musicians with hearing disorders use hearing protectors more frequently. In addition, the musicians questioned suffered from different hearing disorders. Education is needed to change musicians' opinion of hearing conservation and hearing protectors. The education must be directed to both the musicians and the administration of the symphony orchestras.


Gene expression analysis of human induced pluripotent stem cell-derived neurons carrying copy number variants of chromosome 15q11-q13.1.
Duplications of the chromosome 15q11-q13.1 region are associated with an estimated 1 to 3% of all autism cases, making this copy number variation (CNV) one of the most frequent chromosome abnormalities associated with autism spectrum disorder (ASD). Several genes located within the 15q11-q13.1 duplication region including ubiquitin protein ligase E3A (UBE3A), the gene disrupted in Angelman syndrome (AS), are involved in neural function and may play important roles in the neurobehavioral phenotypes associated with chromosome 15q11-q13.1 duplication (Dup15q) syndrome. We have generated induced pluripotent stem cell (iPSC) lines from five different individuals containing CNVs of 15q11-q13.1. The iPSC lines were differentiated into mature, functional neurons. Gene expression across the 15q11-q13.1 locus was compared among the five iPSC lines and corresponding iPSC-derived neurons using quantitative reverse transcription PCR (qRT-PCR). Genome-wide gene expression was compared between neurons derived from three iPSC lines using mRNA-Seq. Analysis of 15q11-q13.1 gene expression in neurons derived from Dup15q iPSCs reveals that gene copy number does not consistently predict expression levels in cells with interstitial duplications of 15q11-q13.1. mRNA-Seq experiments show that there is substantial overlap in the genes differentially expressed between 15q11-q13.1 deletion and duplication neurons, Finally, we demonstrate that UBE3A transcripts can be pharmacologically rescued to normal levels in iPSC-derived neurons with a 15q11-q13.1 duplication. Chromatin structure may influence gene expression across the 15q11-q13.1 region in neurons. Genome-wide analyses suggest that common neuronal pathways may be disrupted in both the Angelman and Dup15q syndromes. These data demonstrate that our disease-specific stem cell models provide a new tool to decipher the underlying cellular and genetic disease mechanisms of ASD and may also offer a pathway to novel therapeutic intervention in Dup15q syndrome.


Chemoenzymatic synthesis of optically active phenolic 3,4-dihydropyridin-2-ones: a way to access enantioenriched 1,4-dihydropyridine and benzodiazepine derivatives.
A chemoenzymatic approach for the synthesis of optically active 4-(3-acetoxyphenyl)-5-(alkoxycarbonyl)-6-methyl-3,4-dihydropyridin-2-ones (3,4-DHP-2-ones) and their hydroxyphenyl derivatives has been developed, the key step being a Candida rugosa lipase (CRL)-catalyzed hydrolysis reaction. As a result, different optically active 3,4-DHP-2-ones have been prepared with very high enantiomeric excesses (ee = 94-99%) and good yields. The enantioenriched 3,4-DHP-2-ones have easily been converted into highly functionalized (R)- and (S)-1,4-dihydropyridines (1,4-DHPs) by means of a Vilsmeier-Haack reaction. Finally, the coupling of the 1,4-DHPs with benzene-1,2-diamine using TFA as an acid promoter provided us the corresponding optically active hybrid 1,5-benzodiazepine-1,4-dihydropyridine (BZD-DHP) derivatives. No racemization took place in these processes and all optically active compounds were obtained in excellent yields.


Multi-platform mass spectrometry analysis of the CSF and plasma metabolomes of rigorously matched amyotrophic lateral sclerosis, Parkinson's disease and control subjects.
Amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) are protein-aggregation diseases that lack clear molecular etiologies. Biomarkers could aid in diagnosis, prognosis, planning of care, drug target identification and stratification of patients into clinical trials. We sought to characterize shared and unique metabolite perturbations between ALS and PD and matched controls selected from patients with other diagnoses, including differential diagnoses to ALS or PD that visited our clinic for a lumbar puncture. Cerebrospinal fluid (CSF) and plasma from rigorously age-, sex- and sampling-date matched patients were analyzed on multiple platforms using gas chromatography (GC) and liquid chromatography (LC)-mass spectrometry (MS). We applied constrained randomization of run orders and orthogonal partial least squares projection to latent structure-effect projections (OPLS-EP) to capitalize upon the study design. The combined platforms identified 144 CSF and 196 plasma metabolites with diverse molecular properties. Creatine was found to be increased and creatinine decreased in CSF of ALS patients compared to matched controls. Glucose was increased in CSF of ALS patients and α-hydroxybutyrate was increased in CSF and plasma of ALS patients compared to matched controls. Leucine, isoleucine and ketoleucine were increased in CSF of both ALS and PD. Together, these studies, in conjunction with earlier studies, suggest alterations in energy utilization pathways and have identified and further validated perturbed metabolites to be used in panels of biomarkers for the diagnosis of ALS and PD.


Biomarkers for Bisphosphonate-Related Osteonecrosis of the Jaw.
The aim of this study was to investigate a possible biomarker for bisphosphonate-related osteonecrosis of the jaw (BRONJ) in an animal model. Forty-eight Sprague-Dawley rats were randomly divided into the bisphosphonate group (n = 36), who were injected once a week with zoledronic acid, and the control group (n = 12), who were injected once a week with saline. After 6 weeks, surgical intervention was performed, and injections were continued up to 8 weeks. Rats in the bisphosphonate group were then further classified to the ONJ group, and the non-ONJ group, and biomarkers, including CTx, Glu-OC, TRACP 5b, RANKL, and OPG, were assessed at baseline (T0), at surgical intervention (T1), and at sacrifice (T2). Histomorphometric analysis for quantification of osteoclasts was performed. Repeated measures analysis of variance revealed that TRACP 5b levels and the RANKL/OPG ratio were significantly decreased over time in the ONJ group compared with the non-ONJ group (p < .05). At T2, the area under the curve was 0.807 for TRACP 5b (sensitivity: 88.9%, specificity 66.7% at cutoff) and 0.765 for the RANKL/OPG ratio (sensitivity: 77.8%, specificity 62.9% at cutoff). TRACP 5b showed a lower least significant change (29.6%) with lower intra-assay coefficient of variability (CV; 6.32%) and interassay CV (11.20%) compared with those of the RANKL/OPG ratio (39.27%) and showed a higher signal-to-noise ratio (2.76) than that of the RANKL/OPG ratio (1.62). N.Oc/T.Ar and N.Oc/B.Ar demonstrated significantly decreased number of osteoclasts in ONJ group versus non-ONJ group. These results show that serum TRACP 5b and the RANKL/OPG ratio were possible biomarkers for BRONJ. These data may provide useful additional information for future ONJ research. Further studies are needed to validate these results in humans with ONJ.


Secular and seasonal trends in obesity in Chilean preschool children, 1996-2004.
Chile is a unique example of the nutrition transition, with improvements in undernutrition and subsequent rapid increases in obesity occurring at a rate much faster than in other countries. This study aims to describe the cross-sectional obesity trends in Chilean preschool children from 1996 to 2004. Anthropometric measurements from preschool children (ages 2-5) registered in the Junta Nacional de Jardines Infantiles program from 1996 to 2004 were analysed. The weight-for-height z score using the World Health Organization 1977/1985 reference curves for age, sex, height, and weight were defined to estimate overweight and obesity. The overall trends in obesity were described for each study year and generalized estimating equation models were used to describe trends in obesity after adjusting for the correlated nature of repeated measurements in individual children in consecutive years. The prevalence of obese and overweight children has remained constant in both boys and girls during the past 9 years; however, after adjustment for repeated measurements in individual children, the odds of obesity increased by 30% each year (odds ratio [OR] 1.28, 95% confidence interval [CI] 1.27-1.31, P < 0.001). Furthermore, the odds of obesity were significantly greater in both August and November compared with March. The prevalence of obesity in Chilean preschool children continues to be a major public health concern, and cross-sectional trends may underestimate the magnitude of the problem.


Anxiety and Depression in Bidirectional Relations Between Pain and Smoking: Implications for Smoking Cessation.
Pain and tobacco smoking are highly prevalent and comorbid conditions that impose considerable burdens on individuals and health care systems. A recently proposed reciprocal model suggests that these conditions interact in a bidirectional manner, resulting in greater pain and the maintenance of tobacco addiction. Anxiety and depression are common among smokers in pain and have been identified as central mechanisms of interest. There is emerging evidence that smokers with anxiety/depression may experience more severe pain and functional impairment, greater pain-induced motivation to smoke, and increased sensitivity to pain during periods of smoking abstinence. Based on empirical findings, we hypothesize that these experiences may engender expectations that abstaining from smoking will exacerbate both pain and negative affect, thus eroding self-efficacy for smoking cessation and increasing perceived barriers to quitting. The goal of this narrative review is to examine the role of anxiety/depression in complex pain-smoking relations so as to advance evolving theoretical perspectives and inform the development of tailored interventions.


[Assessment of clinical diagnostic accuracy for skin cancer].
There is an increase in the incidence rates of skin cancer in Chile. To study the clinical diagnostic accuracy (CDA) for skin cancer. CDA was defined as the percentage of agreement between clinical and pathological diagnosis. Approximately 600,000 pathological reports from five hospitals in Santiago were reviewed. A total of 2,593 skin tumours; 230 Malignant Melanoma (MM); 412 Squamous Cell Carcinoma (SCC) and 1,951 Basal Cell Carcinoma (BCC) were studied. These tumours were clinically diagnosed and surgically treated by dermatologists. The CDA was studied for each tumour, by the anatomical localization of the tumour, Breslow Index in MM, by age and sex of the patient. The highest CDA was observed for BCC (76.2%); followed by MM (64.3%) and SCC (34.7%). By anatomical localization, for MM the highest CDA was observed in the soles (p < 0.05); for BCC, the highest CDA was in the face (p < 0.05). No significant differences were observed in SCC. By age, for MM, the CDA was higher in patients aged less than 50 years. No differences in CDA by age were observed in the other two tumours. By sex, no differences were found. A higher CDA was found in MM with Breslow indexes III and IV than for MM with Breslow indexes I and II. CDA is affected by the clinical variables analyzed in this study. A more accurate clinical diagnosis of skin cancer could be obtained taking into account these variables.


Left ventricular diastolic dysfunction as a cause of congestive heart failure. Mechanisms and management.
To define the mechanisms underlying left ventricular diastolic dysfunction in patients with congestive heart failure and normal systolic function and to identify the patients at risk for this syndrome. Studies were selected that describe the clinical observations of congestive heart failure with normal systolic function and that provide experimental and clinical insights into the mechanisms responsible for ventricular diastolic dysfunction. Recent studies indicate that a large number of patients (up to 40% in some series) presenting with congestive heart failure have preserved left ventricular systolic function. The factors contributing to altered left ventricular diastolic function include fibrosis, hypertrophy, ischemia, and increased afterload. The latter three factors, alone or in combination, predispose to impaired left ventricular relaxation, an active energy-requiring process. Thus, decreased left ventricular diastolic distensibility (increased diastolic pressure at any level of diastolic volume) may arise not only from altered passive elastic properties stemming from fibrosis or increased muscle mass but also from derangements in the dynamics of ventricular relaxation. In patients with essential hypertension, all four of the above mechanisms may be operative. Considering the prevalence of hypertension in the general population, hypertension appears to be an important underlying factor in many patients with heart failure on the basis of diastolic mechanisms. In the patient presenting with dyspnea and elevated filling pressures, but with a nondilated, normally contracting ventricle, treatment with standard heart failure medications (such as digitalis, diuretics, and vasodilators) is often ineffective and may be deleterious. Such patients may respond more favorably to beta-blockers and calcium-channel blockers. Diastolic dysfunction should be considered in the patient presenting with heart failure symptoms but with normal systolic function, particularly in hypertensive patients with left ventricular hypertrophy.


Flight altitudes of a soaring bird suggest landfill sites as power line collision hotspots.
Anthropogenic structures are increasingly encroaching wildlife habitats, creating conflicts between humans and animals. Scaling up renewable energy requires new infrastructures such as power lines, that cause high mortality among birds since they act as obstacles to flight and are used for perching and nesting, which can result in collisions or electrocutions. These interactions often endanger wildlife populations and may also result in high financial costs for companies. Flight behaviour plays a crucial role in collision risk, and the study of flight altitudes enables us to understand what drives birds to fly at collision risk altitudes. This allows the identification of high-risk areas, conditions and bird behaviours, and the implementation of mitigation measures by power line companies. In this study, we use boosted random tree modelling to identify drivers of white stork (Ciconia ciconia) flight altitudes and to investigate the factors that lead them to fly at collision risk altitudes. We found that the main drivers of flight altitude for this soaring bird species were time of day, distance to the nearest landfill site and cloud cover density. Bird age, habitat type and season were comparatively less important. Collision risk increases during crepuscular hours near landfill sites, also in days with high cloud cover density and during the breeding season. In recent years, hundreds to thousands of storks congregate daily at landfill sites to take advantage of the predictability and superabundance of anthropogenic food waste. Some of these sites have high density of power lines, becoming collision risk hotspots for storks and other landfill users. Despite being susceptible to collision, our results suggest that white storks can avoid power lines to a certain extent, by changing their flight altitude at ca. 80 m from these structures. This study shows that the implementation of mitigation measures for existing power lines should be prioritized in areas in the vicinity of landfill sites within white stork distribution ranges, and the projection of new lines should avoid those areas. These measures would benefit species vulnerable to mortality due to power line collision, and it would also reduce associated power outages and economic costs.


Classical hallucinogens as antidepressants? A review of pharmacodynamics and putative clinical roles.
Hallucinogens have been part of spiritual practice for millennia, but controversy surrounding their mind-manifesting effects led to their proscription by the mid-20th century, largely without evidence of harm or toxicity and despite nascent data suggesting therapeutic utility in treating depressive illnesses. This review explores their pharmacodynamic actions and the current limited data on their clinic effectiveness. These drugs appear to exert their psychedelic effects through their agonist or partial agonist activity at the serotonergic 5-HT2A receptor, though they also have affinity for other metabotropic serotonin receptors. Hallucinogen binding affects a wide range of intracellular signalling pathways, the precise nature of which remains incompletely understood. They alter the serotonergic tone of brainstem raphe nuclei that project through the brain; they interact with receptors in the prefrontal cortex altering connectivity patterns and intracellular functioning; and they disrupt inhibitory control of sensory input via the thalamus to the cortex. The serotonergic system has long been implicated in anxiety and depressive disorders, and is a major target of most existing antidepressants. Classical hallucinogens alter the functioning of this system, but not in the same way current medications do: whilst there are identified receptors and neurotransmitter pathways through which hallucinogens could therein produce therapeutic effects, the neurobiology of this remains speculative at this time. There is currently an extremely limited but growing literature on hallucinogen safety and clinical application. The drugs appear well tolerated by healthy controls and clinical populations, and the rapid tolerance to repeated administration might reduce the possibility of dependency. Clinical trials reported over the past decade have generally shown positive therapeutic potential, but they are notably few in number. Legislative policy has had a freezing effect on evaluation of these compounds, a better understanding of which might improve our knowledge of the processes involved in consciousness, the neuropathology of depression, and potentially open up new pharmacological therapies.


Engaging nurses in smoking cessation: Challenges and opportunities in Turkey.
This paper discusses the training of nurses in smoking cessation as part of routine patient care in Turkey. Formative research was carried out prior to training to identify challenges faced by smokers when trying to quit. Site visits to government hospitals and cessation clinics were conducted to observe health care provider-patient interactions involving behavior change. Four culturally sensitive cessation training workshops for nurses (n = 54) were conducted in Istanbul. Following training, nurses were debriefed on their experiences delivering cessation advice. Challenges to cessation counseling included lack of time and incentives for nurse involvement; lack of skills to deliver information about the harm of smoking and benefits of quitting; the medicalization of cessation through the use of pharmaceuticals; and hospital policy which devalues time spent on cessation activities. The pay-for-performance model currently adopted in hospitals has de-incentivized doctor participation in cessation clinics. Nurses play an important role in smoking cessation in many countries. In Turkey, hospital policy will require change so that cessation counseling can become a routine part of nursing practice, incentives for providing cessation are put in place, and task sharing between nurses and doctors is clarified. Nurses and doctors need to receive training in both the systemic harms of smoking and cessation counseling skills. Opportunities, challenges and lessons learned are highlighted.


Regression dilution bias: tools for correction methods and sample size calculation.
Random errors in measurement of a risk factor will introduce downward bias of an estimated association to a disease or a disease marker. This phenomenon is called regression dilution bias. A bias correction may be made with data from a validity study or a reliability study. In this article we give a non-technical description of designs of reliability studies with emphasis on selection of individuals for a repeated measurement, assumptions of measurement error models, and correction methods for the slope in a simple linear regression model where the dependent variable is a continuous variable. Also, we describe situations where correction for regression dilution bias is not appropriate. The methods are illustrated with the association between insulin sensitivity measured with the euglycaemic insulin clamp technique and fasting insulin, where measurement of the latter variable carries noticeable random error. We provide software tools for estimation of a corrected slope in a simple linear regression model assuming data for a continuous dependent variable and a continuous risk factor from a main study and an additional measurement of the risk factor in a reliability study. Also, we supply programs for estimation of the number of individuals needed in the reliability study and for choice of its design. Our conclusion is that correction for regression dilution bias is seldom applied in epidemiological studies. This may cause important effects of risk factors with large measurement errors to be neglected.


The promises of quantitative systems pharmacology modelling for drug development.
Recent growth in annual new therapeutic entity (NTE) approvals by the U.S. Food and Drug Administration (FDA) suggests a positive trend in current research and development (R&D) output. Prior to this, the cost of each NTE was considered to be rising exponentially, with compound failure occurring mainly in clinical phases. Quantitative systems pharmacology (QSP) modelling, as an additional tool in the drug discovery arsenal, aims to further reduce NTE costs and improve drug development success. Through in silico mathematical modelling, QSP can simulate drug activity as perturbations in biological systems and thus understand the fundamental interactions which drive disease pathology, compound pharmacology and patient response. Here we review QSP, pharmacometrics and systems biology models with respect to the diseases covered as well as their clinical relevance and applications. Overall, the majority of modelling focus was aligned with the priority of drug-discovery and clinical trials. However, a few clinically important disease categories, such as Immune System Diseases and Respiratory Tract Diseases, were poorly covered by computational models. This suggests a possible disconnect between clinical and modelling agendas. As a standard element of the drug discovery pipeline the uptake of QSP might help to increase the efficiency of drug development across all therapeutic indications.


Protein kinase C and rho activated coiled coil protein kinase 2 (ROCK2) modulate Alzheimer's APP metabolism and phosphorylation of the Vps10-domain protein, SorL1.
Generation of the amyloid β (Aβ) peptide of Alzheimer's disease (AD) is differentially regulated through the intracellular trafficking of the amyloid β precursor protein (APP) within the secretory and endocytic pathways. Protein kinase C (PKC) and rho-activated coiled-coil kinases (ROCKs) are two "third messenger" signaling molecules that control the relative utilization of these two pathways. Several members of the Vps family of receptors (Vps35, SorL1, SorCS1) play important roles in post-trans-Golgi network (TGN) sorting and generation of APP derivatives, including Aβ at the TGN, endosome and the plasma membrane. We now report that Vps10-domain proteins are candidate substrates for PKC and/or ROCK2 and act as phospho-state-sensitive physiological effectors for post-TGN sorting of APP and its derivatives. Analysis of the SorL1 cytoplasmic tail revealed multiple consensus sites for phosphorylation by protein kinases. SorL1 was subsequently identified as a phosphoprotein, based on sensitivity of its electrophoretic migration pattern to calf intestine alkaline phosphatase and on its reaction with anti-phospho-serine antibodies. Activation of PKC resulted in increased shedding of the ectodomains of both APP and SorL1, and this was paralleled by an apparent increase in the level of the phosphorylated form of SorL1. ROCK2, the neuronal isoform of another protein kinase, was found to form complexes with SorL1, and both ROCK2 inhibition and ROCK2 knockdown enhanced generation of both soluble APP and Aβ. These results highlight the potential importance of SorL1 in elucidating phospho-state sensitive mechanisms in the regulation of metabolism of APP and Aβ by PKC and ROCK2.


The evolution and maintenance of monoecy and dioecy in Sagittaria latifolia (Alismataceae).
Plant species rarely exhibit both monoecious and dioecious sexual systems. This limits opportunities to investigate the consequences of combined versus separate sex function on mating patterns and genetic variation and the analysis of factors responsible for the evolution and maintenance of the two sexual systems. Populations of the North American clonal aquatic Sagittaria latifolia are usually either monoecious or dioecious and often grow in close geographic proximity. We investigated mating patterns, genetic structure, and relationships between the two sexual systems using allozyme variation in populations from southern Ontario, Canada. As predicted, selfing rates in monoecious populations (n = 6, mean = 0.41) were significantly higher than in dioecious populations (n = 6, mean = 0.11). Moreover, marker-based estimates of inbreeding depression (delta) indicated strong selection against inbred offspring in both monoecious (mean delta = 0.83) and dioecious (mean delta = 0.84) populations. However, the difference in selfing rate between the sexual systems was not reflected in contrasting levels of genetic variation. Our surveys of 12 loci in 15 monoecious and 11 dioecious populations revealed no significant differences in the proportion of polymorphic loci (P), number of alleles per locus (A), or observed and expected heterozygosity (H(o) and H(e), respectively). Strong inbreeding depression favoring survival of outcrossed offspring may act to maintain similar levels of diversity between monoecious and dioecious populations. Despite geographical overlap between the two sexual systems in southern Ontario, a dendrogram of genetic relationships indicated two distinct clusters of populations largely corresponding to monoecious and dioecious populations. Reproductive isolation between monoecious and dioecious populations appears to be governed, in part, by observed differences in habitat and life history. We suggest that selfing and inbreeding depression in monoecious populations are important in the transition from monoecy to dioecy and that the maintenance of distinct sexual systems in S. latifolia is governed by interactions between ecology, life history, and mating.


Concurrent loss of chromosome arm 1p and chromosome 3 predicts a decreased disease-free survival in uveal melanoma patients.
Uveal melanoma is a highly malignant disease with a mortality rate of 50% at 10 to 15 years. Previous studies have shown that chromosomal changes are associated with decreased survival of the patient. However, in these studies the small number of tumors analyzed did not allow robust statistical analysis. In the present study, the independent numerical changes in chromosomes 1, 3, 6, and 8 on disease-free survival (DFS) was assessed in a large series of patients with uveal melanoma. One hundred twenty tumors from patients with uveal melanoma were analyzed for numerical changes in chromosomes 1, 3, 6, and 8, with cytogenetic analysis, fluorescent in situ hybridization, and/or comparative genomic hybridization. Data were correlated with disease outcome in univariate and multivariate analyses, by Kaplan-Meier and Cox regression analyses. At a mean follow-up time of 45 months, 42 patients had died or had metastatic disease. In the univariate analysis, loss of chromosome 3, gain of 8q, largest tumor diameter, or the presence of epithelioid cells was associated with a decreased DFS. In the multivariate analysis, the effect of monosomy 3 on survival was largely modified by changes in 1p36. Regarding all chromosomal changes, only the concurrent loss of the short arm of chromosome 1 and all of chromosome 3 was an independent prognostic parameter for disease-free survival (P < 0.001). In uveal melanoma, concurrent loss of the short arm of chromosome 1 and all of chromosome 3 is an independent predictor of decreased DFS.


Fermented Papaya Preparation Restores Age-Related Reductions in Peripheral Blood Mononuclear Cell Cytolytic Activity in Tube-Fed Patients.
Tube-fed elderly patients are generally supplied with the same type of nutrition over long periods, resulting in an increased risk for micronutrient deficiencies. Dietary polyphenols promote immunity and have anti-inflammatory, anti-carcinogenic, and anti-oxidative properties. Carica papaya Linn. is rich in several polyphenols; however, these polyphenols are poorly absorbed from the digestive tract in their original polymerized form. Therefore, we determined the molecular components of a fermented Carica papaya Linn. preparation, as well as its effects on immunity and the composition of gut microbiota in tube-fed patients. Different doses of the fermented C. papaya L. preparation were administered to three groups of tube-fed patients for 30 days. Its effects on fecal microbiota composition and immunity were assessed by 16S rRNA gene sequencing and immune-marker analysis, respectively. The chemical composition of the fermented C. papaya L. preparation was analyzed by capillary electrophoresis- and liquid chromatography- time of flight mass spectrometry. The fermented C. papaya L. preparation restored peripheral blood mononuclear cell (PBMC) cytolytic activity; however, no other biomarkers of immunity were observed. Treatment with the preparation (9 g/day) significantly reduced the abundance of Firmicutes in the fecal microbiota. In particular, treatment reduced Clostridium scindens and Eggerthella lenta in most patients receiving 9 g/day. Chemical analysis identified low-molecular-weight phenolic acids as polyphenol metabolites; however, no polymerized, large-molecular-weight molecules were detected. Our study indicates that elderly patients who are tube-fed over the long-term have decreased PBMC cytolytic activity. In addition, low-molecular-weight polyphenol metabolites fermented from polymerized polyphenols restore PBMC cytolytic activity and modulate the composition of gut microbiota in tube-fed patients.


Variation in pediatric stereoelectroencephalography practice among pediatric neurosurgeons in the United States: survey results.
Stereoelectroencephalography (SEEG) has become widespread in the United States during the past decade. Many pediatric neurosurgeons practicing SEEG may not have had experience with this technique during their formal training, and the literature is mostly limited to single-center series. As a result, implementation of this relatively new technique may vary at different institutions. The authors hypothesized that aspects of SEEG experience, techniques, and outcomes would vary widely among programs across the country. An electronic survey with 35 questions addressing the categories of training and experience, technique, electrode locations, and outcomes was sent to 128 pediatric epilepsy surgeons who were potential SEEG users. Sixty-one pediatric fellowship-trained epilepsy surgeons in the United States responded to the survey. Eighty-nine percent were actively using SEEG in their practice. Seventy-two percent of SEEG programs were in existence for less than 5 years, and 68% were using SEEG for > 70% of their invasive monitoring. Surgeons at higher-volume centers operated on younger patients (p < 0.001). Most surgeons (70%) spent 1-3 hours per case planning electrode trajectories. Two-thirds of respondents reported a median implant duration of 5-7 days, but 16% reported never having an implant duration > 5 days, and 16% reported having had implants stay in place for > 4 weeks. The median response for the median number of electrodes initially implanted was 12 electrodes, although 19% of respondents reported median implants of 5-8 electrodes and 17% reported median implants of 15-18 electrodes. Having a higher volume of SEEG cases per year was associated with a higher median number of electrodes implanted (p < 0.001). Most surgeons found SEEG helpful in defining an epileptic network and reported that most of their SEEG patients undergo focal surgical treatment. SEEG has been embraced by the pediatric epilepsy surgery community. Higher case volume is correlated with a tendency to place more electrodes and operate on younger patients. For most parameters addressed in the survey, responses from surgeons clustered around a norm, though additional findings of substantial variations highlight differences in implementation and philosophy among pediatric epilepsy programs.


Mesothelioma incidence projections in South East England.
We estimated the past and future age-standardised incidence rates of mesothelioma by birth cohort and by period of diagnosis in South East England. We extracted data on patients diagnosed with mesothelioma (International Classification of Diseases-10 C45) between 1960 and 2009 from the Thames Cancer Registry. We calculated the age-standardised incidence rates using the European standard population. We used age-cohort and age-period modelling to estimate the age-specific incidence rates for the 1900 to 1950 birth cohorts and the 1935 to 2034 calendar periods. A much more pronounced increase in mesothelioma incidence between 1972 and 2007 was observed in males than in females. In both sexes, the incidence rates increased in successive generations up to the 1945 birth cohort. Projection of rates in the future showed an increase in incidence in males until 2022 and a decrease thereafter. Among females, the incidence rate was predicted to increase gradually until reaching its maximum around 2027, and to remain stable thereafter. The occurrence of mesothelioma is closely linked to occupational exposure to asbestos in the 1960s and 1970s and, due to the long latency period, the incidence of mesothelioma is projected to increase until the 2020s.


Prenatal care and childbirth assistance in Amazonian women before and after the Pacific Highway Construction (2003-2011): a cross-sectional study.
Attention to prenatal care and child delivery is important for the health of women and children, but in the Amazon these indicators tend to be historically unfavorable, in part by geographical and political isolation. In 2003 both Brazilian and Peru governments have finished paving an international road connecting remotes areas in the Brazilian Amazon to the Pacific coast in Peru. The situation of prenatal care and child delivery with mothers of children under 5 years old living in the urban area of Assis Brasil, Acre was assessed in two cross-sectional studies performed in 2003 and 2011, corresponding to the period before and after the Pacific highway construction. In 2003, most mothers were of black/Afro-American ethnicity, or "pardos" (the offspring of a Caucasian with a African descendant) (77.69 %), had more than 4 years of schooling (73.40 %) and had a mean age of 22.18 years. In 2011, the number of as a migration of indigenous women increased from 0 to 14.40 % of the respondents, because of migration from communities along the rivers to urban areas, with no other significant changes in maternal characteristics. No significant improvement in childbirth assistance was noticed between 1997 and 2011; only the percentage of in-hospital vaginal deliveries performed by doctors increased from 17.89 to 66.26 % (p <0.001) during this period. Access to prenatal care was associated with white ethnicity in 2003, and higher socioeconomic level and white ethnicity in 2011, while the higher number of prenatal visits was associated with higher maternal education and higher socioeconomic levels in 2011. Vaginal child delivery at a hospital facility was associated with maternal age in 2003, and year of birth, being of white ethnicity and higher level of education in 2011. The indicators of prenatal care and child delivery were below the national average, showing that geographical isolation still affects women's health care in the Amazon, despite the construction of the highway and governmental health protocols adopted during this period.


Nivolumab Combined With Brentuximab Vedotin for Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma: Efficacy and Safety From the Phase II CheckMate 436 Study.
Primary mediastinal B-cell lymphoma (PMBL) is a rare but aggressive non-Hodgkin lymphoma with poor outcomes in patients with relapsed/refractory (R/R) disease. PMBL is characterized by high expression of programmed death-1 ligand and variable expression of CD30. Nivolumab, an anti-programmed death-1 immune checkpoint inhibitor, and brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate, may have synergistic activity in R/R PMBL. The expansion cohort of the open-label, phase I/II CheckMate 436 study enrolled patients with confirmed R/R PMBL who were previously treated with either autologous hematopoietic cell transplantation or two or more prior chemotherapy regimens if ineligible for autologous hematopoietic cell transplantation. Patients received nivolumab (240 mg intravenously) and BV (1.8 mg/kg intravenously) every 3 weeks until disease progression or unacceptable toxicity. Primary end points were investigator-assessed objective response rate (ORR) per the Lugano 2014 criteria and safety. Thirty patients with PMBL were treated and evaluable. At a median follow-up of 11.1 months, ORR (95% CI) was 73% (54% to 88%), with a 37% complete remission rate per investigator, and ORR of 70% (51% to 85%), with a 43% complete metabolic response rate per independent review. Median duration of response, median progression-free survival, and median overall survival have not been reached. Eleven responders had consolidation with autologous (n = 5) or allogeneic (n = 6) transplantation. Treatment-related adverse events were reported in 25 patients (83%). Sixteen patients (53%) had grade 3 to 4 treatment-related adverse events; the most common were neutropenia (n = 9), thrombocytopenia (n = 3), and peripheral neuropathy (n = 3). There were no treatment-related deaths. In patients with R/R PMBL, the combination of nivolumab plus BV represents a promising option, with high antitumor activity and a manageable safety profile.


Gastric Peptides-Gastrin and Somatostatin.
Gastric acid secretion (i) facilitates digestion of protein as well as absorption of micronutrients and certain medications, (ii) kills ingested microorganisms, including Helicobacter pylori, and (iii) prevents bacterial overgrowth and enteric infection. The principal regulators of acid secretion are the gastric peptides gastrin and somatostatin. Gastrin, the major hormonal stimulant for acid secretion, is synthesized in pyloric mucosal G cells as a 101-amino acid precursor (preprogastrin) that is processed to yield biologically active amidated gastrin-17 and gastrin-34. The C-terminal active site of gastrin (Trp-Met-Asp-Phe-NH2 ) binds to gastrin/CCK2 receptors on parietal and, more importantly, histamine-containing enterochromaffin-like (ECL) cells, located in oxyntic mucosa, to induce acid secretion. Histamine diffuses to the neighboring parietal cells where it binds to histamine H2 -receptors coupled to hydrochloric acid secretion. Gastrin is also a trophic hormone that maintains the integrity of gastric mucosa, induces proliferation of parietal and ECL cells, and is thought to play a role in carcinogenesis. Somatostatin, present in D cells of the gastric pyloric and oxyntic mucosa, is the main inhibitor of acid secretion, particularly during the interdigestive period. Somatostatin exerts a tonic paracrine restraint on gastrin secretion from G cells, histamine secretion from ECL cells, and acid secretion from parietal cells. Removal of this restraint, for example by activation of cholinergic neurons during ingestion of food, initiates and maximizes acid secretion. Knowledge regarding the structure and function of gastrin, somatostatin, and their respective receptors is providing novel avenues to better diagnose and manage acid-peptic disorders and certain cancers. Published 2020. Compr Physiol 10:197-228, 2020.


Association of Gestational Weight Gain and Maternal Body Mass Index in Early Pregnancy With Risk for Nonaffective Psychosis in Offspring.
Prenatal exposure to famine is associated with a 2-fold risk for nonaffective psychoses. Less is known about whether maternal nutrition states during pregnancy modify offspring risk for nonaffective psychoses in offspring in well-fed populations. To determine whether gestational weight gain (GWG) during pregnancy and maternal body mass index (BMI) in early pregnancy are associated with risk for nonaffective psychoses in offspring. This population-based cohort study used data from Swedish health and population registers to follow up 526 042 individuals born from January 1, 1982, through December 31, 1989, from 13 years of age until December 31, 2011. Cox proportional hazards regression models adjusted for socioeconomic status and potential risk factors were used to examine the risk for developing nonaffective psychoses. Family-based study designs were used to further test causality. Data were analyzed from February 1 to May 14, 2016. Gestational weight gain during pregnancy, maternal body mass index at the first antenatal visit, and paternal body mass index at the time of conscription into the Swedish military (at 18 years of age). Hazard ratios (HRs) for the diagnosis of nonaffective psychoses (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] codes F20 to F29 and International Classification of Diseases, Ninth Revision [ICD-9] codes 295, 297 and 298, except 298A and 298B) and narrowly defined schizophrenia (ICD-9 code 295 and ICD-10 code F20). The 526 042 individuals in the cohort (48.52% female and 51.47% male; mean [SD] age, 26 [2.3] years) included 2910 persons with nonaffective psychoses at the end of follow-up, of whom 704 had narrowly defined schizophrenia. Among the persons with nonaffective psychosis, 184 (6.32%) had mothers with extremely inadequate GWG (<8 kg for mothers with normal baseline BMI), compared with 23 627 (4.52%) of unaffected individuals. Extremely inadequate GWG was associated with an increased risk for nonaffective psychoses among offspring in adjusted models (HR, 1.32; 95% CI, 1.13-1.54) and in matched-sibling analysis (HR, 1.61; 95% CI, 1.02-2.56). Similar patterns were observed when considering narrowly defined schizophrenia as the outcome. Maternal mild thinness in early pregnancy was weakly associated with an increased risk for nonaffective psychosis in offspring (HR for BMI≥17.0 and <18.5, 1.21; 95% CI, 1.01-1.45), as was paternal severe thinness (HR for BMI<16.0, 2.53; 95% CI, 1.26-5.07) in mutually adjusted models. In matched-sibling analysis, no association was observed between maternal underweight (HR, 1.46; 95% CI, 0.90-2.35), overweight (HR, 1.11; 95% CI, 0.73-1.68), or obesity (HR, 0.56; 95% CI, 0.23-1.38) and risk for nonaffective psychosis in offspring. Inadequate GWG was associated with an increased risk for nonaffective psychosis in offspring, consistent with historical studies on maternal starvation. These findings support the role of maternal undernutrition in nonaffective psychosis pathogenesis.


Apoptosis induced by p75NTR overexpression requires Jun kinase-dependent phosphorylation of Bad.
The p75 neurotrophin receptor (p75NTR), a member of the tumor necrosis factor receptor superfamily, facilitates apoptosis during development and after injury to the CNS. The signaling cascades activated by p75NTR that result in apoptosis remain poorly understood. In this study, we show that overexpression of p75NTR in primary cortical neurons, in pheochromocytoma cell line (PC12) cells, and in glioma cells results in activation of Jun kinase (JNK), accumulation of cytochrome c within the cytosol, and activation of caspases 9, 6, and 3. To link p75NTR-dependent JNK activation to mitochondrial cytochrome c release, regulation of BH3-domain-only family members was examined. Transcription of BH3-domain-only family members was not induced by p75NTR, but p75NTR-dependent JNK activation resulted in phosphorylation and oligomerization of the BH3-domain-only family member Bad. Loss of function experiments using Bad dominant negatives or RNA interference demonstrated a requirement for Bad in p75NTR-induced apoptosis. Together, these studies provide the first data linking apoptosis induced by p75NTR to the phosphorylation of BH3-domain-only family members.


Functions of the Lyn tyrosine kinase in health and disease.
Src family kinases such as Lyn are important signaling intermediaries, relaying and modulating different inputs to regulate various outputs, such as proliferation, differentiation, apoptosis, migration and metabolism. Intriguingly, Lyn can mediate both positive and negative signaling processes within the same or different cellular contexts. This duality is exemplified by the B-cell defect in Lyn-/- mice in which Lyn is essential for negative regulation of the B-cell receptor; conversely, B-cells expressing a dominant active mutant of Lyn (Lynup/up) have elevated activities of positive regulators of the B-cell receptor due to this hyperactive kinase. Lyn has well-established functions in most haematopoietic cells, viz. progenitors via influencing c-kit signaling, through to mature cell receptor/integrin signaling, e.g. erythrocytes, platelets, mast cells and macrophages. Consequently, there is an important role for this kinase in regulating hematopoietic abnormalities. Lyn is an important regulator of autoimmune diseases such as asthma and psoriasis, due to its profound ability to influence immune cell signaling. Lyn has also been found to be important for maintaining the leukemic phenotype of many different liquid cancers including acute myeloid leukaemia (AML), chronic myeloid leukaemia (CML) and B-cell lymphocytic leukaemia (BCLL). Lyn is also expressed in some solid tumors and here too it is establishing itself as a potential therapeutic target for prostate, glioblastoma, colon and more aggressive subtypes of breast cancer. LAY To relay information, a cell uses enzymes that put molecular markers on specific proteins so they interact with other proteins or move to specific parts of the cell to have particular functions. A protein called Lyn is one of these enzymes that regulate information transfer within cells to modulate cell growth, survival and movement. Depending on which type of cell and the source of the information input, Lyn can positively or negatively regulate the information output. This ability of Lyn to be able to both turn on and turn off the relay of information inside cells makes it difficult to fully understand its precise function in each specific circumstance. Lyn has important functions for cells involved in blood development, including different while blood cells as well as red blood cells, and in particular for the immune cells that produce antibodies (B-cells), as exemplified by the major B-cell abnormalities that mice with mutations in the Lyn gene display. Certain types of leukaemia and lymphoma appear to have too much Lyn activity that in part causes the characteristics of these diseases, suggesting it may be a good target to develop new anti-leukaemia drugs. Furthermore, some specific types, and even specific subtypes, of solid cancers, e.g. prostate, brain and breast cancer can also have abnormal regulation of Lyn. Consequently, targeting this protein in these cancers could also prove to be beneficial.


Significance and taxonomic value of iso and anteiso monoenoic fatty acids and branded beta-hydroxy acids in Desulfovibrio desulfuricans.
The fatty acids obtained from extractable lipids of the anaerobic sulfate bacterium Desulfovibrio desulfuricans were identified. Saturated and monoenoic iso (C15-C19) and anteiso (C15, C17) fatty acids and saturated normal (C14-C18) and monoenoic normal (C16, C18) fatty acids were shown to be shown to be present by capillary gas chromatography-mass spectrometry. Iso and anteiso beta-hydroxy fatty acids were analyzed as trimethylsilyl ethers in the same way. The position of methyl branches in the monoenoic fatty acids was determined from characteristic fragment ions in the mass spectra of their methyl esters. Disilyloxy methyl esters, prepared by derivatization of the mono unsaturated methyl esters and analyzed by capillary gas chromatography-mass spectrometry, provided the position of double bonds. The monoenoic fatty acids identified in this way were normal (delta7-C16:1, delta9-C16:1, delta9-C18:1, delta11-C18:1), iso (delta7-C15:1, delta9-C16:1, delta9-C17:1, delta11-C18:1, delta11-C19:1), and anteiso (delta7-C15:1, delta9-C17:1). Iso delta9-C17:1 fatty acid is present as the major component. The occurrence of these monoenoic fatty acids in this bacterium is of taxonomical importance.


Therapist-Assisted Internet-Based Cognitive Behavioral Therapy Versus Progressive Relaxation in Obsessive-Compulsive Disorder: Randomized Controlled Trial.
Obsessive-compulsive disorder (OCD) is a highly disabling psychological disorder with a chronic course if left untreated. Cognitive behavioral therapy (CBT) has been shown to be an effective treatment, but access to face-to-face CBT is not always possible. Internet-based CBT (iCBT) has become an increasingly viable option. However, no study has compared iCBT to an analogous control condition using a randomized controlled trial (RCT). A 2-armed RCT was used to compare a therapist-assisted 12-module iCBT to an analogous active attention control condition (therapist-assisted internet-based standard progressive relaxation training, iPRT) in adult OCD. This paper reports pre-post findings for OCD symptom severity. In total, 179 participants (117 females, 65.7%) were randomized (stratified by gender) into iCBT or iPRT. The iCBT intervention included psychoeducation, mood and behavioral management, exposure and response prevention (ERP), cognitive therapy, and relapse prevention; the iPRT intervention included psychoeducation and relaxation techniques as a way of managing OCD-related anxiety but did not incorporate ERP or other CBT elements. Both treatments included audiovisual content, case stories, demonstrations of techniques, downloadable audio content and worksheets, and expert commentary. All participants received 1 weekly email, with a maximum 15-minute preparation time per client from a remote therapist trained in e-therapy. Emails aimed to monitor progress, provide support and encouragement, and assist in individualizing the treatment. Participants were assessed for baseline and posttreatment OCD severity with the telephone-administered clinician-rated Yale-Brown Obsessive-Compulsive Scale and other measures by assessors who were blinded to treatment allocation. No pretreatment differences were found between the 2 conditions. Intention-to-treat analysis revealed significant pre-post improvements in OCD symptom severity for both conditions (P<.001). However, relative to iPRT, iCBT showed significantly greater symptom severity improvement (P=.001); Cohen d for iCBT was 1.05 (95% CI 0.72-1.37), whereas for iPRT it was 0.48 (95% CI 0.22-0.73). The iCBT condition was superior in regard to reliable improvement (25/51, 49% vs 16/55, 29%; P=.04) and clinically significant pre-post-treatment changes (17/51, 33% vs 6/55, 11%; P=.005). Those undertaking iCBT post completion of iPRT showed further significant symptom amelioration (P<.001), although the sequential treatment was no more efficacious than iCBT alone (P=.63). This study is the first to compare a therapist-assisted iCBT program for OCD to an analogous active attention control condition using iPRT. Our findings demonstrate the large magnitude effect of iCBT for OCD; interestingly, iPRT was also moderately efficacious, albeit significantly less so than the iCBT intervention. The findings are compared to previous internet-based and face-to-face CBT treatment programs for OCD. Future directions for technology-enhanced programs for the treatment of OCD are outlined. Australian New Zealand Clinical Trials Registry ACTRN12611000321943; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=336704 (Archived by WebCite at http://www.webcitation.org/70ovUiOmd).


Physiotherapy pain curricula in Finland: a faculty survey.
Background and aims Despite the recognition of pain as a global health problem and advancements achieved in what is known about effective pain management, pain education for undergraduate health care professionals remains insufficient. This study investigated the content of pain curricula and the time allocated to pain education on physiotherapy programs at bachelor's level at Universities of Applied Sciences (UASs) in Finland. Methods A web-based survey questionnaire was sent to the directors of the physiotherapy programs at all the Finnish UASs (n=15) where physiotherapy is taught at bachelor's level. The questionnaire consisted of 14 questions covering basic concepts and the science of pain, pain assessment, pain management, and the adequacy of pain curricula. Each UAS completed one questionnaire i.e. returned one official opinion. Results The response rate was 80% (n=12). The mean for the total number of contact hours of pain education was 74 (standard deviation 34.2). All UASs had integrated pain education. In addition to this 42% (n=5) of the UASs had a separate pain course. The UASs offering such a course over and above the integrated pain education had twice the amount of pain content education compared to those UASs that only had integrated pain education (mean 103 h vs. 53 h, p=0.0043). Most of the education was devoted to conditions where pain is commonly a feature, manual therapy, and electrical agents for pain control. The biopsychosocial model of pain, cognitive behavioral methods of pain management, physician management, and multidisciplinary management were the least covered topics. Five UASs (42%) payed attention to the International Association for the Study of Pain curriculum outline and only 33% (n=4) considered their pain education to be sufficient. Conclusions Our results indicate that more contact hours are devoted to pain education on the Finnish UASs' physiotherapy programs at bachelor's level, than has previously been reported in faculty surveys. A separate pain course is one way to ensure a sufficient amount of pain education. Overall, despite a sufficient time devoted to pain education, some essential pain contents were inadequately covered. Implications The study contributes information on how pain education can be organized on physiotherapy programs at undergraduate level. Besides a sufficient amount of pain education, which can be ensured by a separate pain course, attention should be paid to pain education content being up-to-date. This could help in estimating the different proportions of pain content needed in educational settings. Efforts should also be made at keeping integrated pain education well-coordinated and purposeful. There is a need for further research estimating the effectiveness of pain education according to the different ways in which it is organized. There is also a need to investigate whether more hours allocated to pain education results in better understanding and professional skills.


Genetic integrity of cryopreserved plant cells: a review.
Cryopreservation techniques exist for some 100-plant species. Cryopreservation for the long-term conservation of in vitro germplasm results in the exposure of tissues to physical, chemical and physiological stresses causing cryoinjury. Although, the effects of cryoinjury upon the genome are often unknown, any accumulative DNA polymorphisms may not be induced by cryopreservation per se but are the result of the whole culture-cryoprotection-regeneration process. It is desirable to assess the genetic integrity of plants surviving cryogenic storage to determine if they are true to type after cryopreservation. This can be done at the phenotypic, histological, cytological, biochemical and molecular levels. The relevance of these approaches to stability investigations is discussed with their limitations. This review provides a definition for Cryobionomics - a novel term describing the re-modelled concept of genetic stability and the re-introduction of cryopreserved plants into the environment.


Not the next IRA: how health savings accounts shape public opinion.
Scholars suspect that public policies affect public opinion, but the empirical evidence is mixed, and contemporary theories advance offsetting predictions. This study examines two allegedly similar private investment account programs that differ in politically relevant ways. Statistical analyses show that owners of Individual Retirement Accounts (IRAs) and Health Savings Accounts (HSAs) experience policy feedback effects, but in opposite directions. More specifically, matched comparisons of respondents in a national survey indicate that IRA participants are more likely to favor Social Security privatization than individuals without IRAs. In contrast, HSA participants are less likely to prefer consumer-driven health coverage in which individuals are empowered to make choices. Overall, the findings suggest that policies alter public opinion preferences but that the effects depend on programmatic design and performance.


The X chromosome in quantitative trait locus mapping.
The X chromosome requires special treatment in the mapping of quantitative trait loci (QTL). However, most QTL mapping methods, and most computer programs for QTL mapping, have focused exclusively on autosomal loci. We describe a method for appropriate treatment of the X chromosome for QTL mapping in experimental crosses. We address the important issue of formulating the null hypothesis of no linkage appropriately. If the X chromosome is treated like an autosome, a sex difference in the phenotype can lead to spurious linkage on the X chromosome. Further, the number of degrees of freedom for the linkage test may be different for the X chromosome than for autosomes, and so an X chromosome-specific significance threshold is required. To address this issue, we propose a general procedure to obtain chromosome-specific significance thresholds that controls the genomewide false positive rate at the desired level. We apply our methods to data on gut length in a large intercross of mice carrying the Sox10Dom mutation, a model of Hirschsprung disease. We identified QTL contributing to variation in gut length on chromosomes 5 and 18. We found suggestive evidence of linkage to the X chromosome, which would be viewed as strong evidence of linkage if the X chromosome was treated as an autosome. Our methods have been implemented in the package R/qtl.


Bartonella vinsonii subsp. berkhoffii and Bartonella henselae bacteremia in a father and daughter with neurological disease.
Bartonella vinsonii subsp. berkhoffii is an important, emerging, intravascular bacterial pathogen that has been recently isolated from immunocompetent patients with endocarditis, arthritis, neurological disease and vasoproliferative neoplasia. Vector transmission is suspected among dogs and wild canines, which are the primary reservoir hosts. This investigation was initiated to determine if pets and family members were infected with one or more Bartonella species. PCR and enrichment blood culture in Bartonella alpha Proteobacteria growth medium (BAPGM) was used to determine infection status. Antibody titers to B. vinsonii subsp. berkhoffii genotypes I-III and B. henselae were determined using a previously described indirect fluorescent antibody test. Two patients were tested sequentially for over a year to assess the response to antibiotic treatment. Intravascular infection with B. vinsonii subsp. berkhoffii genotype II and Bartonella henselae (Houston 1 strain) were confirmed in a veterinarian and his daughter by enrichment blood culture, followed by PCR and DNA sequencing. Symptoms included progressive weight loss, muscle weakness, lack of coordination (the father) and headaches, muscle pain and insomnia (the daughter). B. vinsonii subsp. berkhoffii genotype II was also sequenced from a cerebrospinal fluid BAPGM enrichment culture and from a periodontal swab sample. After repeated courses of antibiotics, post-treatment blood cultures were negative, there was a decremental decrease in antibody titers to non-detectable levels and symptoms resolved in both patients. B. vinsonii subsp. berkhoffii and B. henselae are zoonotic pathogens that can be isolated from the blood of immunocompetent family members with arthralgias, fatigue and neurological symptoms. Therapeutic elimination of Bartonella spp. infections can be challenging, and follow-up testing is recommended. An increasing number of arthropod vectors, including biting flies, fleas, keds, lice, sandflies and ticks have been confirmed or are suspected as the primary mode of transmission of Bartonella species among animal populations and may also pose a risk to human beings.


Getting results used: evidence from reproductive health programmatic research in Guatemala.
This article reviews 44 operations research projects aiming to improve reproductive health services in Guatemala, conducted by the Population Council from 1988 to 2001. It documents the experience of the research programme, traces the extent to which research results are identifiable in existing programmes, and analyses factors influencing utilization. Utilization of research results occurs as a gradual process of information sharing, where researchers influence decision-makers through a continual stream of information rather than a single set of findings. Utilization depends on leadership, collaborative planning and implementation, close monitoring, and feasible research designs, among other factors. To influence policy formulation, organizations should form enduring links among institutions and develop critical research skills among personnel who collaborate with or manage service programmes. To understand how operations research affects policy and programme change, one must consider not just individual projects, but rather the synergistic impact of multiple projects on a broad range of themes over time.


Is developmental and behavioral pediatrics training related to perceived responsibility for treating mental health problems?
The aim of this study was to investigate training in developmental and behavioral pediatrics (DBP) for graduating residents, their competencies in diagnosing and treating child mental health (MH) problems, and whether the amount of DBP training and/or perceived competencies are associated with perceived responsibility for treating 3 MH problems. Data were collected from 636 residents who completed the American Academy of Pediatrics's 2007 Graduating Residents Survey. The survey included questions on training and self-rated competencies in multiple MH skill areas and perceived responsibility for identifying and treating/managing children's MH problems. Weighted multivariable logistic regression analyses examined associations between training, competencies, and perceived responsibility for treating/managing attention-deficit/hyperactivity disorder (ADHD), anxiety, and depression. Ninety percent of respondents completed a DBP rotation, with 86% reporting >3 to 4 weeks of training. Duration of DBP rotation was related to training and perceived competencies in MH skill areas, and nearly all residents who reported high competencies were trained in those skill areas. However, <50% reported their competencies as "very good" or "excellent." Residents with training and high competency in dosing with medications were most likely to agree that pediatricians should be responsible for treating/managing ADHD, anxiety, and depression. DBP training is highly associated with self-rated MH competencies, and highly assessed competencies are related to perceived responsibility for treating/managing common MH problems; yet 14% of graduating residents have <3 to 4 weeks of DBP training. These results argue for providing more high-quality educational experience with proven effectiveness to produce confident pediatricians who will be more responsive to identifying and treating MH problems of their patients.


Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia.
Over the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR) <1.15). We conducted a large-scale coordinated international collaboration to combine independent genotyping data to improve the statistical power and aid in robust discovery of GWS loci. This study uses genome-wide genotyping data from a discovery sample (7387 ASD cases and 8567 controls) followed by meta-analysis of summary statistics from two replication sets (7783 ASD cases and 11359 controls; and 1369 ASD cases and 137308 controls). We observe a GWS locus at 10q24.32 that overlaps several genes including PITX3, which encodes a transcription factor identified as playing a role in neuronal differentiation and CUEDC2 previously reported to be associated with social skills in an independent population cohort. We also observe overlap with regions previously implicated in schizophrenia which was further supported by a strong genetic correlation between these disorders (Rg = 0.23; P = 9 × 10-6). We further combined these Psychiatric Genomics Consortium (PGC) ASD GWAS data with the recent PGC schizophrenia GWAS to identify additional regions which may be important in a common neurodevelopmental phenotype and identified 12 novel GWS loci. These include loci previously implicated in ASD such as FOXP1 at 3p13, ATP2B2 at 3p25.3, and a 'neurodevelopmental hub' on chromosome 8p11.23. This study is an important step in the ongoing endeavour to identify the loci which underpin the common variant signal in ASD. In addition to novel GWS loci, we have identified a significant genetic correlation with schizophrenia and association of ASD with several neurodevelopmental-related genes such as EXT1, ASTN2, MACROD2, and HDAC4.


Allergology in Europe, the blueprint.
The number of patients with allergic diseases in Europe, and thus relevant demand for health care, is continuously increasing. In this EAACI-UEMS position paper, a rationale is given for the medical specialty of allergology. General practitioners and general paediatricians usually cannot elucidate and address all causative factors. Throughout Europe, therefore, the expertise of allergologists (allergists) is required. In collaboration with other medical professionals, they take care of allergic patients, in private practices or in specialized public centres. A well-structured collaboration between allergists and allergy centres offers the possibility of rapid signalling of new trends developing in the population of allergic patients (e.g., in food and drug allergy). Allergy centres also can perform clinical (and basic) research, teach medical students, future allergists and provide postgraduate training. To prevent that the quality of care in one or several countries within Europe lags behind developments in other countries, the UEMS Section and Board on Allergology together with the European Academy of Allergy and Clinical Immunology advocates the status of a full specialty of allergology in each European country, with a further intention to align their activities (blueprint, curriculum and centre visitation) with the UEMS Section of Paediatrics.


Regulation of human bone marrow-derived osteoprogenitor cells by osteogenic growth factors.
Human bone marrow contains a distinct cell population that expresses bone proteins and responds to transforming growth factor beta 1 (TGF-beta), but not to hematopoietic growth factors (Long, M. W., J. L. Williams, and K. G. Mann. 1990. J. Clin. Invest. 86:1387-1395). We now report the isolation, characterization, and growth factor responsiveness of these precursors to human osteoblasts and the identification of a human osteoprogenitor cell. Immunological separation of human bone marrow nonadherent low-density (NALD) cells results in a marked enrichment of cells that express osteocalcin, osteonectin, and bone alkaline phosphatase. Flow cytometric analyses show that distinct cell subpopulations exist among these isolated cells. The majority of the bone antigen-positive cells are approximately the size of a lymphocyte, whereas other, less frequent antibody-separated subpopulations consist of osteoblast-like cells and osteoprogenitor cells. In serum-free cultures, TGF-beta stimulates the small, antigen-positive cells to become osteoblast-like, as these cells both increase in size, and express increased levels of osteocalcin and alkaline phosphatase. Antibody-separated cells also contain a separate population of clonal progenitor cells that form colonies of osteoblast-like cells when cultured in serum-free, semi-solid media. Two types of human osteoprogenitor cells are observed: a colony-forming cell (CFC) that generates several hundred bone antigen-positive cells, and a more mature cluster-forming cell that has a lesser proliferative potential and thus generates clusters of 20-50 antigen-positive cells. Osteopoietic colony-forming cells and cluster-forming cells have an obligate but differential requirement for osteogenic growth factors. The CFCs respond to TGF-beta, basic fibroblast growth factor (bFGF), bone morphogenic protein-2 (BMP-2), and 1, 25-dihydroxy vitamin D3 (1,25-OH D3). In contrast to the colony-forming cells, cluster-forming cells are regulated predominantly by 1,25-OH D3 and TGF-beta, but fail to respond to bFGF. We conclude that human bone marrow contains a nonhematogenous, heterogeneous population of bone precursor cells among which exists a population of proliferating osteoprogenitor cells. Further characterization of these bone precursor cell populations should yield important information on their role in osteogenesis in both health and disease.


Head and Neck Microsurgeon Practice Patterns and Perceptions Regarding Venous Thromboembolism Prophylaxis.
Patients undergoing head and neck (H&N) microvascular reconstruction comprise a population at high risk for venous thromboembolism (VTE). Free flap and VTE thromboprophylaxis may coincide but tend to vary from surgeon to surgeon. This study identifies VTE prophylaxis patterns and perceptions among H&N microsurgeons in the United States. An online survey on VTE prophylaxis practice patterns and perceptions was emailed to 172 H&N microsurgeons in the United States using an anonymous link. There were 74 respondents (43% response rate). These surgeons completed residencies in otolaryngology (59%), plastic surgery (31%), and oral maxillofacial surgery (7%). Most underwent fellowship training (95%) and have practiced at an academic center (97%) for at least 6 years (58%), performing an average of 42 ± 31 H&N free flap cases per year (range = 1-190). Most adhered to general VTE prophylaxis guidelines (69%) while 11% did not and 20% were unsure. Nearly all surgeons (99%) would provide prophylactic anticoagulation, mostly in the form of subcutaneous heparin (51%) or enoxaparin (44%); 64% additionally used aspirin, while 4% used aspirin alone. The majority of surgeons (68%) reported having postoperative VTE complications, with six surgeons (8%) reporting patient deaths due to pulmonary embolism. A third of the surgeons have encountered VTE prophylaxis-related adverse bleeding events, but most still believe that chemoprophylaxis is important for VTE prevention (92%). While 35% of surgeons were satisfied with their current practice, most would find it helpful to have official prophylactic anticoagulation guidelines specific to H&N free flap cases. The majority of microsurgeons experienced postoperative VTE complications after H&N free flap reconstruction despite the routine use of prophylactic anticoagulation. Though bleeding events are a concern, most surgeons believe chemoprophylaxis is important for VTE prevention and would welcome official guidelines specific to this high-risk population.


Sleep and cognition on everyday functioning in older adults: implications for nursing practice and research.
Nearly 50% of older adults experience difficulty with sleeping, and 21% of older adults also experience cognitive complaints to which sleep difficulties can also contribute to poorer cognitive functioning. Combined, such sleep difficulties and age-related cognitive declines can contribute to poorer performance on everyday activities necessary for independence, quality of life, and successful aging. Activities that may be especially compromised are driving, instrumental activities of daily living, and employment. In nursing practice, it is necessary to understand the relationship between sleep and cognition and what contributes to poorer sleep hygiene and cognitive functioning, whether it is medications and polypharmacy, comorbidities, habits and lifestyle factors, or negative mood. Such an understanding can help nurses provide evidence-based interventions to improve sleep and cognition in older patients. In research, nurses must devise and test ways to improve sleep hygiene and cognitive functioning in older patients with methods such as sleep hygiene education and speed-of-processing training to ameliorate everyday functioning and quality of life.


Efficient Bayesian estimates for discrimination among topologically different systems biology models.
A major effort in systems biology is the development of mathematical models that describe complex biological systems at multiple scales and levels of abstraction. Determining the topology-the set of interactions-of a biological system from observations of the system's behavior is an important and difficult problem. Here we present and demonstrate new methodology for efficiently computing the probability distribution over a set of topologies based on consistency with existing measurements. Key features of the new approach include derivation in a Bayesian framework, incorporation of prior probability distributions of topologies and parameters, and use of an analytically integrable linearization based on the Fisher information matrix that is responsible for large gains in efficiency. The new method was demonstrated on a collection of four biological topologies representing a kinase and phosphatase that operate in opposition to each other with either processive or distributive kinetics, giving 8-12 parameters for each topology. The linearization produced an approximate result very rapidly (CPU minutes) that was highly accurate on its own, as compared to a Monte Carlo method guaranteed to converge to the correct answer but at greater cost (CPU weeks). The Monte Carlo method developed and applied here used the linearization method as a starting point and importance sampling to approach the Bayesian answer in acceptable time. Other inexpensive methods to estimate probabilities produced poor approximations for this system, with likelihood estimation showing its well-known bias toward topologies with more parameters and the Akaike and Schwarz Information Criteria showing a strong bias toward topologies with fewer parameters. These results suggest that this linear approximation may be an effective compromise, providing an answer whose accuracy is near the true Bayesian answer, but at a cost near the common heuristics.


Loss of the Hematopoietic Stem Cell Factor GATA2 in the Osteogenic Lineage Impairs Trabecularization and Mechanical Strength of Bone.
The transcription factor GATA2 is required for expansion and differentiation of hematopoietic stem cells (HSCs). In mesenchymal stem cells (MSCs), GATA2 blocks adipogenesis, but its biological relevance and underlying genomic events are unknown. We report a dual function of GATA2 in bone homeostasis. GATA2 in MSCs binds near genes involved in skeletal system development and colocalizes with motifs for FOX and HOX transcription factors, known regulators of skeletal development. Ectopic GATA2 blocks osteoblastogenesis by interfering with SMAD1/5/8 activation. MSC-specific deletion of GATA2 in mice increases the numbers and differentiation capacity of bone-derived precursors, resulting in elevated bone formation. Surprisingly, MSC-specific GATA2 deficiency impairs the trabecularization and mechanical strength of bone, involving reduced MSC expression of the osteoclast inhibitor osteoprotegerin and increased osteoclast numbers. Thus, GATA2 affects bone turnover via MSC-autonomous and indirect effects. By regulating bone trabecularization, GATA2 expression in the osteogenic lineage may contribute to the anatomical and cellular microenvironment of the HSC niche required for hematopoiesis.


Inhibition of NF-kappaB DNA binding by nitric oxide.
It has been suggested that the NF-kappaB transcription factor family may mediate expression of the gene encoding the cytokine-inducible form of nitric oxide synthase (iNOS). To establish if nitric oxide (NO) could in turn affect activity of NF-kappaB, the ability of NO-donor compounds to influence NF-kappaB DNA binding activity in vitro was investigated. NO-donor compounds sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP) both inhibited the DNA binding activity of recombinant NF-kappaB p50 and p65 homodimers and of p50-p65 heterodimers. Inhibition of NF-kappaB p50 DNA binding by NO-donor compounds involved modification of the conserved redox-sensitive C62 residue, as a C62S p50 mutant was significantly more resistant to SNP-mediated inactivation. Non-reducing SDS-polyacrylamide gel electrophoresis demonstrated that SNP could inhibit p50 DNA binding by mechanisms other than the formation of intersubunit disulphide bonds involving p50 residue C62. Electrospray ionization mass spectrometry of a synthetic NF-kappaB p5O peptide containing the C62 residue suggested that NO gas can modify C62 by S-nitrosylation. This study indicates that NO-donors can directly inhibit the DNA binding activity of NF-kappaB family proteins, suggesting that cellular NO provides another control mechanism for modulating the expression of NF-kappaB-responsive genes.


Near-infrared spectroscopy detects woody breast syndrome in chicken fillets by the markers protein content and degree of water binding.
The muscle syndrome woody breast (WB) impairs quality of chicken fillets and is a challenge to the poultry meat industry. There is a need for online detection of affected fillets for automatic quality sorting in process. Near-infrared spectroscopy (NIRS) is a promising method, and in this study we elucidate the spectral properties of WB versus normal fillets. On a training set of 50 chicken fillets (20 normal, 30 WB), we measured NIR, nuclear magnetic resonance (NMR) T2 relaxation distributions, and crude chemical composition. NIRS could estimate protein in the fillets with an accuracy of ±0.64 percentage points. T2 distributions showed that there was a larger share of free water in WB fillets. This difference in water binding generated a shift and narrowing of the water absorption peak in NIR around 980 nm, quantified by a bound water index (BWI). The correlation between BWI and T2 distributions was 0.78, indicating that NIRS contains information about degree of water binding. Discriminant analysis showed that NIRS obtained 100% correct classification of normal versus WB on the training set, and 96% correct classification on a test set of 52 fillets. The main reason for why NIRS can successfully discriminate between WB and normal fillets is the methods sensitivity to both protein content and degree of water binding in the muscle, both established markers for WB. The classification model can be based on NIR spectra only, calibration against protein is not needed. The affected muscle tissue associated with the WB syndrome is unevenly distributed in the fillets, and this heterogeneity was characterized by NIRS and NMR. Clear differences in water binding properties were found between the superficial 1 cm layer and the deeper layer at 1 to 2 cm depth. Significant differences in protein estimates by NIRS at different measurement points along the chicken fillets were obtained for WB fillets. The findings suggest how to obtain optimal sampling with NIRS for best possible discrimination between WB and normal breast fillets.


Monoclonal gammopathy of undetermined significance.
Significant advances have been made in our understanding of the natural history, pathogenesis, mechanisms of progression and prognosis of monoclonal gammopathy of undetermined significance (MGUS). Although the overall incidence of MGUS progression is 1 per year, it is now possible to more accurately predict the risk of progression based on a new risk-stratification model. However, it is still hard to design chemopreventive trials given that the absolute risk of progression per year is low, even in the high-risk group. Therefore, further improvements in estimating the risk of progression are needed. Roughly 50% of MGUS may originate from primary translocation events at the heavy-chain immunoglobulin locus at chromosome 14q32. In most of the remaining MGUS patients, the initiating event is associated with genomic instability that results in hyperdiploidy of certain odd numbered chromosomes. Cytogenetically distinct subtypes of MGUS may carry significant differences in the risk of progression to malignancy. New markers, such as measures of bone marrow angiogenesis and circulating plasma cells may be additional prognostic factors. A better understanding of the mechanisms underlying the transition of normal plasma cells to the MGUS phenotype, and the transition of MGUS to myeloma or related malignancy, will help identify new risk factors for progression and new targets for chemopreventive interventions.


Mitral suture annuloplasty corrects both annular and subvalvular geometry in acute ischemic mitral regurgitation.
Papillary muscle displacement is an important element in the pathogenesis of ischemic mitral regurgitation (IMR). The effects of standard ring annuloplasty on subvalvular geometry are incompletely understood. The hypothesis was tested that annular reduction with a Panethtype suture annuloplasty would correct both annular and papillary muscle geometric abnormalities during acute left ventricular (LV) ischemia. Eight adult sheep underwent insertion of an adjustable, double-suture Paneth-type mitral annuloplasty and radiopaque markers on the left ventricle, mitral annulus, leaflet edges, and anterior (APM) and posterior (PPM) papillary muscle tips. Immediately after surgey, 3-D marker coordinates were determined during Control conditions and during proximal left circumflex occlusion before and after tightening the annuloplasty suture. Acute IMR (MR grade 0.3 +/- 0.3 to 2.1 +/- 0.4, Control versus Ischemia) was associated with end-systolic LV dilatation (+27 +/- 16 ml, change relative to Control), greater septal-lateral (+4.6 +/- 3.1 cm) and commissure-commissure (+3.3 +/- 1.6 cm) mitral annular diameters, longer anterior (+1.5 +/- 0.9 cm) and posterior (+0.6 +/- 0.9 cm) papillary muscle tethering distances, greater distance from the APM to the anterior commissure (+0.9 +/- 0.8 cm), and shorter distance from the PPM to the poslerior commissure (-1.3 +/- 1.5 cm). Suture annuloplasty corrected the annular and subvalvular changes, and IMR returned to Control levels (0.5 +/- 0.5); only LV end-systolic volume (ESV) was different from Control (+25 +/- 18 ml) (mean +/- SD, p < 0.05 versus Control by RMANOVA and Dunnett's test). Suture annuloplasty corrected ischemia-induced end-systolic distortions of the entire valvular-ventricular complex (i.e. inter-leaflet separation, mitral annular dilatation in both axes, and papillary muscle displacements), and abolished acute IMR, independent of any change in ESV. A better understanding of the effects of annular reduction on papillary muscle geometry may lead to improved subvalvular mitral repair techniques.


From Bits to Images: Inversion of Local Binary Descriptors.
Local Binary Descriptors are becoming more and more popular for image matching tasks, especially when going mobile. While they are extensively studied in this context, their ability to carry enough information in order to infer the original image is seldom addressed. In this work, we leverage an inverse problem approach to show that it is possible to directly reconstruct the image content from Local Binary Descriptors. This process relies on very broad assumptions besides the knowledge of the pattern of the descriptor at hand. This generalizes previous results that required either a prior learning database or non-binarized features. Furthermore, our reconstruction scheme reveals differences in the way different Local Binary Descriptors capture and encode image information. Hence, the potential applications of our work are multiple, ranging from privacy issues caused by eavesdropping image keypoints streamed by mobile devices to the design of better descriptors through the visualization and the analysis of their geometric content.


Survivors of cardiac arrest with good neurological outcome show considerable impairments of memory functioning.
Deficits in cognitive function are a well-known dysfunction in survivors of cardiac arrest. However, data concerning memory function in this neurological vulnerable patient collective remain scarce and inconclusive. Therefore, we aimed to assess multiple aspects of retrospective and prospective memory performance in patients after cardiac arrest. We prospectively enrolled 33 survivors of cardiac arrest, with cerebral performance categories (CPC) 1 and 2 and a control-group (n=33) matched in sex, age and educational-level. To assess retrospective and prospective memory performance we administrated 4 weeks after cardiac arrest the "Rey Adult Learning Test" (RAVLT), the "Digit-Span-Backwards Test", the "Logic-Memory Test" and the "Red-Pencil Test". Results indicate an impairment in immediate and delayed free recall, but not in recognition. However, the overall impairment in immediate recall was qualified by analyzing RAVLT performance, showing that patients were only impaired in trials 4 and 5 of the learning sequence. Moreover, working and prospective memory as well as prose recall were worse in cardiac arrest survivors. Cranial computed tomography was available in 61% of all patients (n=20) but there was no specific neurological damage detectable that could be linked to this cognitive impairment. Episodic long-term memory functioning appears to be particularly impaired after cardiac arrest. In contrast, short-term memory storage, even tested via free-call, seems not to be affected. Based on cranial computed tomography we suggest that global brain ischemia rather than focal brain lesions appear to underlie these effects.


Media components influence viral gene expression assays in human fetal astrocyte cultures.
In vitro neurovirological studies of viral infectivity or viral gene expression may be confounded by the multiple neural cell types and/or fibroblast contamination present in early passage cultures prepared from dissociated human central nervous system (CNS) tissue. We have developed highly enriched astrocyte cultures for neurovirological study by culturing in a serum-free defined medium, B16, supplemented with basic fibroblast growth factor (FGF-2). Subculture in this medium selects against fibroblast proliferation and favors sustained proliferation of a highly enriched glial fibrillary acidic protein (GFAP)-positive cell population. These astrocytes support productive replication of cytomegalovirus (CMV) and transient expression of transfected CMV and human immunodeficiency virus type 1 (HIV-1) viral promoters. By comparison, CNS cultures developed in standard serum-containing medium initially contain predominantly astrocytes, but show increasing contamination with fibroblasts with sequential passage. These cultures support CMV viral synthesis in both fibroblasts and astrocytes, cell types distinguishable only by immunostaining for cell specific antigen. CMV or HIV-1 promoter activities, quantitated by transient gene expression assays, are distinctly lower in CNS cultures maintained in serum-containing medium.


Conspecific chemical cues drive density-dependent metabolic suppression independently of resource intake.
Within species, individuals of the same size can vary substantially in their metabolic rate. One source of variation in metabolism is conspecific density - individuals in denser populations may have lower metabolism than those in sparser populations. However, the mechanisms through which conspecifics drive metabolic suppression remain unclear. Although food competition is a potential driver, other density-mediated factors could act independently or in combination to drive metabolic suppression, but these drivers have rarely been investigated. We used sessile marine invertebrates to test how food availability interacts with oxygen availability, water flow and chemical cues to affect metabolism. We show that conspecific chemical cues induce metabolic suppression independently of food and this metabolic reduction is associated with the downregulation of physiological processes rather than feeding activity. Conspecific cues should be considered when predicting metabolic variation and competitive outcomes as they are an important, but underexplored, source of variation in metabolic traits.


Tomato breeding in the genomics era: insights from a SNP array.
The major bottle neck in genetic and linkage studies in tomato has been the lack of a sufficient number of molecular markers. This has radically changed with the application of next generation sequencing and high throughput genotyping. A set of 6000 SNPs was identified and 5528 of them were used to evaluate tomato germplasm at the level of species, varieties and segregating populations. From the 5528 SNPs, 1980 originated from 454-sequencing, 3495 from Illumina Solexa sequencing and 53 were additional known markers. Genotyping different tomato samples allowed the evaluation of the level of heterozygosity and introgressions among commercial varieties. Cherry tomatoes were especially different from round/beefs in chromosomes 4, 5 and 12. We were able to identify a set of 750 unique markers distinguishing S. lycopersicum 'Moneymaker' from all its distantly related wild relatives. Clustering and neighbour joining analysis among varieties and species showed expected grouping patterns, with S. pimpinellifolium as the most closely related to commercial tomatoes earlier results. Our results show that a SNP search in only a few breeding lines already provides generally applicable markers in tomato and its wild relatives. It also shows that the Illumina bead array generated data are highly reproducible. Our SNPs can roughly be divided in two categories: SNPs of which both forms are present in the wild relatives and in domesticated tomatoes (originating from common ancestors) and SNPs unique for the domesticated tomato (originating from after the domestication event). The SNPs can be used for genotyping, identification of varieties, comparison of genetic and physical linkage maps and to confirm (phylogenetic) relations. In the SNPs used for the array there is hardly any overlap with the SolCAP array and it is strongly recommended to combine both SNP sets and to select a core collection of robust SNPs completely covering the entire tomato genome.