Care staff perceptions of a social robot called Paro and a look-alike Plush Toy: a descriptive qualitative approach.
Social robots such as Paro, a therapeutic companion robot, have recently been introduced into dementia care as a means to reduce behavioural and psychological symptoms of dementia. The purpose of this study was to explore care staff perceptions of Paro and a look-alike non-robotic animal, including benefits and limitations in dementia care. The study assumed a descriptive qualitative approach, nested within a large cluster-randomised controlled trial. We interviewed a subsample of 20 facility care staff, from nine long-term care facilities in Southeast Queensland, Australia. Thematic analysis of the data, which was inductive and data-driven, was undertaken with the assistance of the qualitative software, ATLAS.ti®. The findings refer to four categories: increasing excitement for Paro and decreasing enthusiasm for Plush Toy; value and function of Paro; opportunities for engagement; and alternatives vs. robustness. Staff caring for people with dementia preferred Paro compared to a look-alike Plush Toy. Staff identified that Paro had the potential to improve quality of life for people with dementia, whereas the Plush Toy had limitations when compared to Paro. However, participants expressed concern that the cost of Paro could reduce opportunities for use within aged care.


User-held personalised information for routine care of people with severe mental illness.
It is important to seek cost-effective methods of improving the care and outcome of those with serious mental illnesses. User-held records, where the person with the illness holds all or some personal information relating to the course and care of their illness, are now the norm in some clinical settings. Their value for those with severe mental illnesses is unknown. To evaluate the effects of personalised, accessible, user-held clinical information for people with a severe mental illness (defined as psychotic illnesses). We updated previous searches by searching the Cochrane Schizophrenia Group Trials Register in August 2011. This register is compiled by systematic searches of major databases, and handsearches of journals and conference proceedings. We included all relevant randomised controlled trials (RCTs) that:i. have recruited adult participants with a diagnosis of a severe mental illness (specifically psychotic illnesses and severe mood disorders such as bipolar and depression with psychotic features); andii. compared any personalised and accessible clinical information held by the user beyond standard care to standard information routinely held such as appointment cards and generic information on diagnosis, treatment or services available. Study selection and data extraction were undertaken independently by two authors and confirmed and checked by a third. We contacted authors of trials for additional and missing data. Where possible, we calculated risk ratios (RR) and 95% confidence intervals (CI). We used a random-effects model. We assessed risk of bias for included studies and created a 'Summary of findings' table using GRADE. Four RCTs (n = 607) of user-held records versus treatment as usual met the inclusion criteria. When the effect of user-held records on psychiatric hospital admissions was compared with treatment as usual in four studies, the pooled treatment effect showed no significant impact of the intervention and was of very low magnitude (n = 597, 4 RCTs, RR 0.99 CI 0.71 to 1.38, moderate quality evidence). Similarly, there was no significant effect of the intervention in three studies which investigated compulsory psychiatric hospital admissions (n = 507, 4 RCTs, RR 0.64 CI 0.37 to 1.10, moderate quality evidence). Other outcomes including satisfaction and mental state were investigated but pooled estimates were not obtainable due to skewed or poorly reported data, or only being investigated by one study. Two outcomes (violence and death) were not investigated by the included studies. Two important randomised studies are ongoing. The evidence gap remains regarding user-held, personalised, accessible clinical information for people with psychotic illnesses for many of the outcomes of interest. However, based on moderate quality evidence, this review suggests that there is no effect of the intervention on hospital or outpatient appointment use for individuals with psychotic disorders. The number of studies is low, however, and further evidence is required to ascertain whether these results are mediated by the type of intervention, such as involvement of a clinical team or the type of information included.


Role of the redox protein thioredoxin in cytoprotective mechanism evoked by (-)-deprenyl.
Through the inhibition of monoamine oxidase type B (MAO-B), (-)-deprenyl (selegiline) prevents the conversion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to the toxic metabolite 1-methyl-4-phenylpyridinium ion (MPP+) and also prevents the neurotoxicity in the dopaminergic neurons in animal models. Cumulative observations suggest that selegiline may also protect against MPP+-induced neurotoxicity, possibly through the induction of pro-survival genes. We have observed that thioredoxin (Trx) mediates the induction of mitochondrial manganese superoxide dismutase (MnSOD) and Bcl-2 during preconditioning-induced hormesis. We therefore investigated whether the redox protein Trx plays any role in the neuroprotective mechanism of selegiline against MPP+-induced cytotoxicity in human SH-SY5Y neuroblastoma cells and also in primary neuronal cultures of mouse midbrain dopaminergic neurons. After confirming that selegiline protects against MPP+-induced cytotoxicity, we observed further that selegiline, at 1 microM or less, induced Trx for protection against oxidative injury caused by MPP+. The induction of Trx was blocked by protein kinase A (PKA) inhibitor and mediated by a PKA-sensitive phospho-activation of mitogen-activated protein (MAP) kinase Erk1/2 and the transcription factor c-Myc. Selegiline-induced Trx and associated neuroprotection were concomitantly blocked by the antisense against Trx mRNA, but not the sense or antisense mutant phosphothionate oligonucleotides, not only in human SH-SY5Y cells but also in mouse primary neuronal culture of midbrain dopaminergic neurons. Furthermore, the redox cycling of Trx may mediate the protective action of selegiline because the inhibition of Trx reductase by 1-chloro-2,4-dinitrobenzene ameliorated the effect of selegiline. Trx (1 microM) consistently increased the expression of mitochondrial proteins MnSOD and Bcl-2, supporting cell survival (Andoh et al., 2002). In conclusion, without modifying MAO-B activity, selegiline augments the gene induction of Trx, leading to elevated expression of antioxidative MnSOD and antiapoptotic Bcl-2 proteins for protecting against MPP+-induced neurotoxicity.


Association of Fatigue Severity With Maladaptive Coping in Multiple Sclerosis: A Data-Driven Psychodynamic Perspective.
Fatigue in persons with multiple sclerosis (PwMS) is severely disabling. However, the underlying mechanisms remain incompletely understood. Recent research suggests a link to early childhood adversities and psychological trait variables. In line with these studies, this paper took a psychodynamic perspective on MS-fatigue. It was hypothesized that fatigue could represent a manifestation of maladaptive coping with intense emotions. The schema therapeutic mode model served as a theoretical and empirically validated framework, linking psychodynamic theory and empirical research methods. The study was based on a data set of N = 571 PwMS that has also served as the basis for another publication. Data was collected online. The Schema Mode Inventory was used to quantify regulatory strategies to cope with emotionally stressful experiences. In addition, depressive symptoms (Beck's Depression Inventory - FastScreen), physical disability (Patient Determined Disease Steps), alexithymia (Toronto Alexithymia Scale-26), adverse childhood experiences (Childhood Trauma Questionnaire), and self-reported fatigue (Fatigue Scale for Motor and Cognitive Functions) were assessed. Latent profile analysis revealed three distinct groups of PwMS, based on their coping mode profiles: (1) PwMS with low maladaptive coping, (2) PwMS with avoidant/submissive coping styles, and (3) PwMS with avoidant/overcompensatory coping styles. Multivariate comparisons showed no significant difference in physical disability across the three groups. However, heightened levels of self-reported fatigue and depression symptoms occurred in PwMS with maladaptive coping styles. A path model uncovered that self-reported fatigue was robustly related to physical disability (β = 0.33) and detached/avoidant coping (Detached Protector; β = 0.34). There was no specific relation between any of the maladaptive coping modes and depression symptoms. Detached/avoidant coping was in turn predicted by childhood emotional abuse and neglect. The results indicate that childhood adversity and detached/avoidant coping styles may be associated with variability in MS-fatigue severity: PwMS that resort to detached/avoidant coping in response to negative emotions also tend to report heightened levels of fatigue, although they do not differ in their perceived disability from PwMS with low levels of fatigue and maladaptive coping. A link between MS-fatigue and the psychodynamic traumatic conversion model is discussed. The implications of these findings for therapeutic interventions require further study.


Architectural protein Pita cooperates with dCTCF in organization of functional boundaries in Bithorax complex.
Boundaries in the Bithorax complex (BX-C) of Drosophila delimit autonomous regulatory domains that drive parasegment-specific expression of homeotic genes. BX-C boundaries have two crucial functions: they must block crosstalk between adjacent regulatory domains and at the same time facilitate boundary bypass. The C2H2 zinc-finger protein Pita binds to several BX-C boundaries, including Fab-7 and Mcp To study Pita functions, we have used a boundary replacement strategy by substituting modified DNAs for the Fab-7 boundary, which is located between the iab-6 and iab-7 regulatory domains. Multimerized Pita sites block iab-6↔iab-7 crosstalk but fail to support iab-6 regulation of Abd-B (bypass). In the case of Fab-7, we used a novel sensitized background to show that the two Pita-binding sites contribute to its boundary function. Although Mcp is from BX-C, it does not function appropriately when substituted for Fab-7: it blocks crosstalk but does not support bypass. Mutation of the Mcp Pita site disrupts blocking activity and also eliminates dCTCF binding. In contrast, mutation of the Mcp dCTCF site does not affect Pita binding, and this mutant boundary retains partial function.


Using age-stratified incidence data to examine the transmission consequences of pertussis vaccination.
Pertussis is a highly infectious respiratory disease that has been on the rise in many countries worldwide over the past several years. The drivers of this increase in pertussis incidence remain hotly debated, with a central and long-standing hypothesis that questions the ability of vaccines to eliminate pertussis transmission rather than simply modulate the severity of disease. In this paper, we present age-structured case notification data from all provinces of Thailand between 1981 and 2014, a period during which vaccine uptake rose substantially, permitting an evaluation of the transmission impacts of vaccination. Our analyses demonstrate decreases in incidence across all ages with increased vaccine uptake - an observation that is at odds with pertussis case notification data in a number of other countries. To explore whether these observations are consistent with a rise in herd immunity and a reduction in bacterial transmission, we analyze an age-structured model that incorporates contrasting hypotheses concerning the immunological and transmission consequences of vaccines. Our results lead us to conclude that the most parsimonious explanation for the combined reduction in incidence and the shift to older age groups in the Thailand data is vaccine-induced herd immunity.


Effect of solvent polarity in mechanochemistry: preparation of a conglomerate vs. racemate.
Cocrystallization of racemic dl-tartaric acid (dl-ta) and achiral isoniazid (ISN) was investigated using mechanochemistry. Neat grinding (NG) and liquid-assisted grinding (LAG) in the presence of non-polar liquids result in the formation of a conglomerate (ISN·d-ta/ISN·l-ta); whereas LAG with polar liquids yields racemic salt ISN·dl-ta. The effect of solvent polarity and dipole moment in mechanochemistry is discussed.


Effect of walking exercise on bone metabolism in postmenopausal women with osteopenia/osteoporosis.
The purpose of this prospective study was to determine whether moderate walking exercise in postmenopausal women with osteopenia/osteoporosis would affect bone metabolism. Fifty postmenopausal women, aged 49-75 years, with osteopenia/osteoporosis were recruited: 32 women entered the exercise program (the exercise group) and 18 served as controls (the control group). The exercise consisted of daily outdoor walking, the intensity of which was 50% of maximum oxygen consumption, with a duration of at least 1 h with more than 8000 steps, at a frequency of 4 days a week, over a 12-month period. Lumbar (L2-L4) bone mineral density (BMD) was measured at the baseline and every 6 months with dual-energy X-ray absorptiometry (DXA) in both groups. Serum bone-specific alkaline phosphatase (BAP) and urinary cross-linked N-terminal telopeptides of type I collagen (NTX) levels were measured at baseline and at months 1, 3, 6, 9, and 12 by EIA and ELISA, respectively, in the exercise group, and urinary NTX level was measured at the baseline and every 6 months in the control group. There were no significant differences in baseline characteristics including age, height, body weight, bone mass index, years since menopause, lumbar BMD, and urinary NTX level between the two groups. Although no significant changes were observed in lumbar BMD and the urinary NTX level in the control group, lumbar BMD in the exercise group was increased as compared with the control group, but was sustained from the baseline. In the exercise group, the urinary NTX level rapidly responded to walking exercise from month 3, and this reduction was sustained until month 12, followed by reduction in the serum BAP level. A moderately negative correlation was found between the percent change in the urinary NTX level at month 3 and that in lumbar BMD at month 12 in the exercise group. This study clearly demonstrates that the mechanism for the positive response of lumbar BMD to moderate walking exercise in postmenopausal women with osteopenia/osteoporosis appears to be the suppression of bone turnover, and that an early change in the urinary NTX level may be useful to predict the long-term response of increasing lumbar BMD to exercise, although its efficacy for lumbar BMD may be quite modest.


Production of Electrospun Fast-Dissolving Drug Delivery Systems with Therapeutic Eutectic Systems Encapsulated in Gelatin.
Fast-dissolving delivery systems (FDDS) have received increasing attention in the last years. Oral drug delivery is still the preferred route for the administration of pharmaceutical ingredients. Nevertheless, some patients, e.g. children or elderly people, have difficulties in swallowing solid tablets. In this work, gelatin membranes were produced by electrospinning, containing an encapsulated therapeutic deep-eutectic solvent (THEDES) composed by choline chloride/mandelic acid, in a 1:2 molar ratio. A gelatin solution (30% w/v) with 2% (v/v) of THEDES was used to produce electrospun fibers and the experimental parameters were optimized. Due to the high surface area of polymer fibers, this type of construct has wide applicability. With no cytotoxicity effect, and showing a fast-dissolving release profile in PBS, the gelatin fibers with encapsulated THEDES seem to have promising applications in the development of new drug delivery systems.


Don't Assume the Control Group Is Normal-People with Asymptomatic Tendon Pathology Have Higher Pressure Pain Thresholds.
Pain pressure thresholds (PPT) are used to study peripheral and central pain processing. In the tendon, pathological changes may exist without pain. This pilot study aimed to compare PPT between individuals with normal tendons and asymptomatic tendon pathology, and between individuals with and without a history of tendon pain. The patellar, Achilles, and supraspinatus tendons of 128 asymptomatic participants were examined with ultrasound. Global PPT average was determined using a digital algometer at the patellar tendon, quadriceps muscle, L3 spinous process, and deltoid muscle insertion. Participants were separated into three groups: (1) healthy control group (no pathology, no history of pain), (2) tendon pathology at any site without a history of pain, (3) history of tendon pain anywhere. There were 92 controls, seven with asymptomatic pathology and 29 with a history of tendon pain. Asymptomatic tendon pathology at any site (without a history of pain) was associated with globally increased PPTs compared with controls (P < 0.001, pathology N = 7, N = 92 controls). Matched pair analysis remained significant (P < 0.004). A history of tendon pain was associated with globally increased PPTs compared with the control group (P = 0.026). Matched pair analysis was not significant (P = 0.122). Asymptomatic tendon pathology is associated with higher PPTs. These findings point toward central nervous system adaptations but in a novel way-central desensitization. This challenges the validity of conclusions drawn from PPT studies that do not verify normal structure in the control group; artificial inflation of control group data may incorrectly indicate decreased PPTs in the comparison group.


A systematic review of cost-effectiveness analyses of drugs for postmenopausal osteoporosis.
Given the limited availability of healthcare resources and the recent introduction of new anti-osteoporosis drugs, the interest in the cost effectiveness of drugs in postmenopausal osteoporosis remains and even increases. This study aims to identify all recent economic evaluations on drugs for postmenopausal osteoporosis, to critically appraise the reporting quality, and to summarize the results. A literature search using Medline, the National Health Service Economic Evaluation database and the Cost-Effectiveness Analysis Registry was undertaken to identify original articles published between January 1, 2008 and December 31, 2013. Studies that assessed cost effectiveness of drugs in postmenopausal osteoporosis were included. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement was used to assess the quality of reporting of these articles. Of 1,794 articles identified, 39 studies fulfilled the inclusion criteria. They were conducted in 14 different countries and nine active interventions were assessed. When compared with no treatment, active osteoporotic drugs were generally cost effective in postmenopausal women aged over 60-65 years with low bone mass, especially those with prior vertebral fractures. Key drivers of cost effectiveness included individual fracture risk, medication adherence, selected comparators and country-specific analyses. Quality of reporting varied between studies with an average score of 17.9 out of 24 (range 7-21.5). This review found a substantial number of published cost-effectiveness analyses of drugs in osteoporosis in the last 6 years. Results and critical appraisal of these articles can help decision makers when prioritizing health interventions and can inform the development of future economic evaluations.


Physical conditioning programs for improving work outcomes in workers with back pain.
Physical conditioning programs aim to improve work status for workers on sick leave. This is an update of a Cochrane Review (Work conditioning, work hardening and functional restoration for workers with back and neck pain) first published in 2003. To compare the effectiveness of physical conditioning programs in reducing time lost from work for workers with back pain. We searched the following databases to June/July 2008: CENTRAL (The Cochrane Library 2008, issue 3), MEDLINE from 1966, EMBASE from 1980, CINAHL from 1982, PsycINFO from 1967, and PEDro. Randomized controlled trials (RCTs) and cluster RCTs that studied workers with work disability related to back pain and who were included in physical conditioning programs. Two review authors independently extracted data and assessed risk of bias. Thirty-seven references, reporting on 23 RCTs (3676 workers) were included, 13 of which had a low risk of bias. In 14 studies, physical conditioning programs were compared to usual care. In workers with acute back pain, there was no effect on sickness absence. For workers with subacute back pain, we found conflicting results, but subgroup analysis showed a positive effect of interventions with workplace involvement. In workers with chronic back pain, pooled results of five studies showed a small effect on sickness absence at long-term follow-up (SMD: -0.18 (95% CI: -0.37 to 0.00)). In workers with chronic back pain, physical conditioning programs were compared to other exercise therapy in six studies, with conflicting results. The addition of cognitive behavioural therapy to physical conditioning programs was not more effective than the physical conditioning alone. The effectiveness of physical conditioning programs in reducing sick leave when compared to usual care or than other exercises in workers with back pain remains uncertain. In workers with acute back pain, these programs probably have no effect on sick leave, but there may be a positive effect on sick leave for workers with subacute and chronic back pain. Workplace involvement might improve the outcome. Better understanding of the mechanism behind physical conditioning programs and return-to-work is needed to be able to develop more effective interventions.


Increased contrast enhancement of the parent vessel of unruptured intracranial aneurysms in 7T MR imaging.
Inflammation of the arterial wall may lead to aneurysm formation. The presence of aneurysm enhancement on high-resolution vessel wall imaging (HR-VWI) is a marker of wall inflammation and instability. We aim to determine if there is any association between increased contrast enhancement in the aneurysmal wall and its parent artery. Patients with unruptured intracranial aneurysms (UIAs) prospectively underwent 7T HR-VWI. Regions of interest were selected manually and with a semi-automated protocol based on gradient algorithms of intensity patterns. Mean signal intensities in pre- and post-contrast T1-weighted sequences were adjusted to the enhancement of the pituitary stalk and then subtracted to objectively determine: circumferential aneurysmal wall enhancement (CAWE); parent vessel enhancement (PVE); and reference vessel enhancement (RVE). PVE was assessed over regions located 3- and 5 mm from the aneurysm's neck. RVE was assessed in arteries located in a different vascular territory. Twenty-five UIAs were analyzed. There was a significant moderate correlation between CAWE and 5 mm PVE (Pearson R=0.52, P=0.008), whereas no correlation was found between CAWE and RVE (Pearson R=0.20, P=0.33). A stronger correlation was found between CAWE and 3 mm PVE (Pearson R=0.78, P<0.001). Intra-class correlation analysis demonstrated good reliability between measurements obtained using semi-automated and manual segmentation (ICC coefficient=0.790, 95% CI 0.58 to 0.90). Parent arteries exhibit higher contrast enhancement in regions closer to the aneurysm's neck, especially in aneurysms≥7 mm. A localized inflammatory/vasculopathic process in the wall of the parent artery may lead to aneurysm formation and growth.


STATs and gene regulation.
STATs (signal transducers and activators of transcription) are a family of latent cytoplasmic proteins that are activated to participate in gene control when cells encounter various extracellular polypeptides. Biochemical and molecular genetic explorations have defined a single tyrosine phosphorylation site and, in a dimeric partner molecule, an Src homology 2 (SH2) phosphotyrosine-binding domain, a DNA interaction domain, and a number of protein-protein interaction domains (with receptors, other transcription factors, the transcription machinery, and perhaps a tyrosine phosphatase). Mouse genetics experiments have defined crucial roles for each known mammalian STAT. The discovery of a STAT in Drosophila, and most recently in Dictyostelium discoideum, implies an ancient evolutionary origin for this dual-function set of proteins.


NATS-Bench: Benchmarking NAS Algorithms for Architecture Topology and Size.
Neural architecture search (NAS) has attracted a lot of attention and has been illustrated to bring tangible benefits in a large number of applications in the past few years. Architecture topology and architecture size have been regarded as two of the most important aspects for the performance of deep learning models and the community has spawned lots of searching algorithms for both of those aspects of the neural architectures. However, the performance gain from these searching algorithms is achieved under different search spaces and training setups. This makes the overall performance of the algorithms incomparable and the improvement from a sub-module of the searching model unclear. In this paper, we propose NATS-Bench, a unified benchmark on searching for both topology and size, for (almost) any up-to-date NAS algorithm. NATS-Bench includes the search space of 15,625 neural cell candidates for architecture topology and 32,768 for architecture size on three datasets. We analyze the validity of our benchmark in terms of various criteria and performance comparison of all candidates in the search space. We also show the versatility of NATS-Bench by benchmarking 13 recent state-of-the-art NAS algorithms on it. All logs and diagnostic information trained using the same setup for each candidate are provided. This facilitates a much larger community of researchers to focus on developing better NAS algorithms in a more comparable and computationally effective environment. All codes are publicly available at: https://xuanyidong.com/assets/projects/NATS-Bench.


Duabanga-like leaves from the Middle Eocene Princeton chert and comparative leaf histology of Lythraceae sensu lato.
A permineralized lythraceous leaf type found in close association with fruits, stems, and roots of Decodon allenbyensis Cevallos-Ferriz et Stockey in the Middle Eocene Princeton chert of British Columbia, Canada, is described. Midribs have a prominent C-shaped midvein surrounded by sclerenchyma, with an adaxial epidermis of rectangular to rounded cells lacking enlarged mucilage cells. Leaves are dorsiventral, 180-270 μm thick at the lamina, with a double palisade layer. Abaxial epidermal cells have prominent papillae, and these epidermal cells can be infected by fungi, forming dark sterile stromata. Fossil leaves are similar to those of Myrtales and are compared to those of Lythraceae sensu lato. Although these leaves are thought to belong to the previously described Decodon allenbyensis found in the same chert layer, they lack the diagnostic features of extant Decodon leaves. Instead they share most anatomical similarities with Duabanga grandiflora Roxburgh ex DC Walpers (Lythraceae, subfamily Duabangoideae) including vascular tissues, palisade and spongy mesophyll, bundle fibers, and abaxial epidermal papillae. Duabanga grandiflora differs from the fossil in having mucilaginous cells and a consistently V-shaped abaxial midrib. Although anatomically similar to Duabanga, the fossil leaves are considered those of D. allenbyensis, based on association and the depositional environment prior to preservation. Recent phylogenetic analyses place Duabanga and Decodon in separate clades within Lythraceae, but relationships between these clades are not well supported, indicating that fossil leaves should provide useful anatomical characters for elucidating relationships within Lythraceae.


A population of rat liver lysosomes responsible for the selective uptake and degradation of cytosolic proteins.
Two populations of rat liver lysosomes can be distinguished on the basis of their density. A major difference between these populations is that one contains the heat shock cognate protein of 73 kDa (hsc73) within the lysosomal lumen. The lysosomal fraction containing hsc73 exhibits much higher efficiencies in the in vitro uptake and degradation of glyceraldehyde-3-phosphate dehydrogenase and ribonuclease A, two well established substrates of the selective lysosomal pathway of intracellular protein degradation. Preloading of the lysosomal population that is devoid of lumenal hsc73 with hsc73 isolated from cytosol activated the selective transport of substrate proteins into these lysosomes. Furthermore, treatment of animals with leupeptin, an inhibitor of lysosomal cathepsins, or 88 h of starvation also increased the amount of hsc73 within their lysosomal lumen, and these in vivo treatments also activated the selective transport of substrate proteins in vitro. Thus, the hsc73 located within lysosomes appears to be required for efficient uptake of cytosolic proteins by these organelles. The difference in hsc73 content between the lysosomal populations appears to be due to differences in their ability to take up hsc73 combined with differences in the intralysosomal degradation rates of hsc73. The increased stability of hsc73 in one population of lysosomes is primarily a consequence of this lysosomal population's more acidic pH.


Assessment of beetle diversity, community composition and potential threats to forestry using kairomone-baited traps.
Traps designed to capture insects during normal movement/dispersal, or via attraction to non-specific (plant) volatile lures, yield by-catch that carries valuable information about patterns of community diversity and composition. In order to identify potential native/introduced pests and detect predictors of colonization of non-native pines, we examined beetle assemblages captured in intercept panel traps baited with kairomone lures used during a national monitoring of the woodwasp, Sirex noctilio, in Southern Africa. We identified 50 families and 436 morphospecies of beetles from nine sites sampled in both 2008 and 2009 and six areas in 2007 (trap catch pooled by region) across a latitudinal and elevational gradient. The most diverse groups were mainly those strongly associated with trees, known to include damaging pests. While native species dominated the samples in terms of richness, the dominant species was the introduced bark beetle Orthotomicus erosus (Curculionidae: Scolytinae) (22 ± 34 individuals/site). Four Scolytinae species without previous records in South Africa, namely Coccotrypes niger, Hypocryphalus robustus (formerly Hypocryphalus mangiferae), Hypothenemus birmanus and Xyleborus perforans, were captured in low abundances. Communities showed temporal stability within sites and strong biogeographic patterns across the landscape. The strongest single predictors of community composition were potential evaporation, latitude and maximum relative humidity, while the strongest multifactor model contained elevation, potential evaporation and maximum relative humidity. Temperature, land use variables and distance to natural areas did not significantly correlate with community composition. Non-phytophagous beetles were also captured and were highly diverse (32 families) perhaps representing important beneficial insects.


NOX1 deficiency in apolipoprotein E-knockout mice is associated with elevated plasma lipids and enhanced atherosclerosis.
Nicotinamide adenine dinucleotide phosphate oxidases (NOX) are enzymes that generate reactive oxygen species (ROS). NOX2 activity in the vascular wall is elevated in hypercholesterolemia, and contributes to oxidative stress and atherogenesis. Here we examined the role of another NOX isoform, NOX1, in atherogenesis in apolipoprotein E-knockout (APOE(-/-)) mice fed a Western diet for 14 weeks. Although NOX1 mRNA expression was unchanged in aortas from APOE(-/-) versus wild-type mice, expression of the NOX1-specific organizer, NOXO1, was diminished, consistent with an overall reduction in NOX1 activity in APOE(-/-) mice. To examine the impact of a further reduction in NOX1 activity, APOE(-/-) mice were crossed with NOX1(-/y) mice to generate NOX1(-/y)/APOE(-/-) double-knockouts. NOX1 deficiency in APOE(-/-) mice was associated with 30-50% higher plasma very-low-density lipoprotein (VLDL)/LDL and triglyceride levels (P < 0.01). Vascular ROS levels were also elevated by twofold in NOX1(-/y)/APOE(-/-) versus APOE(-/-) mice (P < 0.05), despite no changes in expression of other NOX subunits. Although en face analysis of the descending aorta revealed no differences in plaque area between NOX1(-/y)/APOE(-/-) and APOE(-/-) mice, intimal thickening in the aortic sinus was increased by 40% (P < 0.05) in the double-knockouts. Moreover, NOX1 deficiency was associated with a less stable plaque phenotype; aortic sinus lesions contained 60% less collagen (P < 0.01), 40% less smooth muscle (P < 0.01), and 2.5-fold higher levels of matrix metalloproteinase-9 (P < 0.001) than lesions in APOE(-/-) mice. Thus, these data, which suggest a protective role for NOX1 against hyperlipidemia and atherosclerosis in APOE(-/-) mice, highlight the complex and contrasting roles of different NOX isoforms (e.g., NOX2 versus NOX1) in vascular pathology.


Kashin Beck Disease: more than just osteoarthrosis: a cross-sectional study regarding the influence of body function-structures and activities on level of participation.
The purpose of this study was to investigate the influence of body function, activities and pain on the level of activity in adults with Kashin Beck Disease (KBD). Seventy-five KBD patients with a mean age of 54.8 years (SD 11.3) participated. Anthropometrics, range of joint motion (ROM) and muscle strength were measured as well as the time-up-and-go test and functional tests for the lower and upper extremities. Activity was assessed with the participation scale and the WHO DAS II. In the shoulder, elbow, hip and knee joints, a severe decrease in ROM and bilateral pain was noted. A decrease in muscle strength was observed in almost all muscles. The timed-up-and-go test scores decreased. No or mild restriction in activity was found in 35%, and 33% experienced a moderate restriction whereas 32% had severe to extreme restriction. Activities in the lower extremities were mildly to moderately correlated to ROM and muscle strength, whereas in the upper extremities activities were correlated to range of joint motion. Activity was significantly associated with ROM after correction for muscle strength, gender and age. Participation was borderline significantly associated with ROM after correction for muscle strength, gender, age and the activity time-up-and-go. In KBD adults, a severe decrease in activity is primarily caused by decrease in ROM. These findings have strong influence on rehabilitation and surgical intervention.


Indirect selection on female extra-pair reproduction? Comparing the additive genetic value of maternal half-sib extra-pair and within-pair offspring.
One specific hypothesis explaining the evolution of extra-pair reproduction (EPR) by socially monogamous females is that EPR is under indirect selection because extra-pair offspring (EPO) sired by extra-pair males have higher additive genetic value for fitness than the within-pair offspring (WPO) a female would have produced had she solely mated with her socially paired male. This hypothesis has not been explicitly tested by comparing additive genetic value between EPO and the WPO they replaced. We show that the difference in additive genetic breeding value (BV) between EPO and the WPO they replaced is proportional to the genetic covariance between offspring fitness and male net paternity gain through EPR, and estimate this covariance with respect to offspring recruitment in free-living song sparrows (Melospiza melodia). Recruitment and net paternity gain showed non-zero additive genetic variance and heritability, and negative genetic covariance. Opposite to prediction, EPO therefore had lower BV for recruitment than the WPO they replaced. We thereby demonstrate an explicit quantitative genetic approach to testing the hypothesis that EPR allows polyandrous females to increase offspring additive genetic value, and suggest that there may be weak indirect selection against female EPR through reduced additive genetic value for recruitment of EPO versus WPO in song sparrows.


Adaptation and growth of Serratia marcescens in contact lens disinfectant solutions containing chlorhexidine gluconate.
Serratia marcescens (11 of 12 strains) demonstrated an ability to grow in certain chlorhexidine-based disinfecting solutions recommended for rigid gas-permeable contact lenses. For a representative strain, cells that were grown in nutrient-rich medium, washed, and inoculated into disinfecting solution went into a nonrecoverable phase within 24 h. However, after 4 days, cells that had the ability to grow in the disinfectant (doubling time, g = 5.7 h) emerged. Solutions supporting growth of S. marcescens were filter sterilized. These solutions, even after removal of the cells, showed bactericidal activity against Pseudomonas aeruginosa and a biphasic survival curve when rechallenged with S. marcescens. Adaptation to chlorhexidine by S. marcescens was not observed in solutions formulated with borate ions. For chlorhexidine-adapted cells, the MIC of chlorhexidine in saline was eightfold higher than that for unadapted cells. Cells adapted to chlorhexidine showed alterations in the proteins of the outer membrane and increased adherence to polyethylene. Cells adapted to chlorhexidine persisted or grew in several other contact lens solutions with different antimicrobial agents, including benzalkonium chloride.


Selection for rehabilitation: acute care discharge patterns for stroke and orthopaedic patients.
This study aimed to develop predictive models to assist clinicians working in acute care to determine which stroke and lower limb orthopaedic patients should be discharged to nursing homes, inpatient rehabilitation, or home. The subjects were 223 patients with stroke and 125 patients with lower limb orthopaedic problems, aged 60 years and over, and the 22 acute care and rehabilitation clinicians who cared for these patients. Patient status was measured within 72 hours of discharge using the Adult FIM(SM) (Guide for the Uniform Data Set for Medical Rehabilitation, 1993) and ten additional items from either the RICFAS (Rehabilitation Institute of Chicago, 1987) or developed for this research. Four mathematical models were developed to predict discharge destination using stepwise discriminant function analysis. Using between three and seven items from the FIM(SM) alone or FIM(SM) plus additional variables, these models correctly classified between 74.9% and 80.5% of patients. In conclusion, clinicians are offered a selection of models to guide their discharge destination decisions for two large groups of patients. While these models cannot replace clinical judgement, they increase the transparency of decisions. The use of objective models to guide clinical decisions are essential, particularly given increasing pressure to justify patient access to costly rehabilitation services.


How Can National Antimicrobial Stewardship Interventions in Primary Care Be Improved? A Stakeholder Consultation.
Many antimicrobial stewardship (AMS) interventions have been implemented in England, facilitating decreases in antibiotic prescribing. Nevertheless, there is substantial variation in antibiotic prescribing across England and some healthcare organizations remain high prescribers of antibiotics. This study aimed to identify ways to improve AMS interventions to further optimize antibiotic prescribing in primary care in England. Stakeholders representing different primary care settings were invited to, and 15 participated in, a focus group or telephone interview to identify ways to improve existing AMS interventions. Forty-five intervention suggestions were generated and 31 were prioritized for inclusion in an online survey. Fifteen stakeholders completed the survey appraising each proposed intervention using the pre-defined APEASE (i.e., Affordability, Practicability, Effectiveness, Acceptability, Safety, and Equity) criteria. The highest-rated nine interventions were prioritized as most promising and feasible, including: quality improvement, multidisciplinary peer learning, appointing AMS leads, auditing individual-level prescribing, developing tools for prescribing audits, improving inductions for new prescribers, ensuring consistent local approaches to antibiotic prescribing, providing online AMS training to all patient-facing staff, and increasing staff time available for AMS work with standardizing AMS-related roles. These prioritized interventions could be incorporated into existing national interventions or developed as stand-alone interventions to help further optimize antibiotic prescribing in primary care in England.


New Insights into the Structure of the Vapor/Water Interface from Large-Scale First-Principles Simulations.
We present extensive ab initio simulations of the molecular arrangements at the vapor/water interface, which provide valuable insights into the interface structure. In particular, the simulations address the controversy of whether there is a significant amount of nondonor configurations at this prototypical interface, using a novel Car-Parrinello-like ab initio molecular dynamics approach. The interface is modeled by a system of 384 water molecules for 125 ps in a two-dimensional periodic slab, the most extensive ab initio molecular dynamics simulation to date. In contrast to previous theoretical simulations and X-ray absorption spectroscopy, but consistent with sum-frequency generation experiments, we observe no evidence for a significant occurrence of acceptor-only species at the vapor/water interface. Besides a distinct surface relaxation effect, we find that only the topmost layers of the interface obey structural order.


Filling and voiding pressures measured by ambulatory monitoring and conventional studies during natural and artificial bladder filling.
A total of 20 men awaiting elective prostatectomy for bladder outflow obstruction underwent conventional medium filling cystometry and ambulatory monitoring of bladder pressures during natural bladder filling. Total bladder capacity was similar during both tests (medium filling cystometry 256 +/- 138 ml. and ambulatory monitoring 248 +/- 120 ml., p not significant) as was the voided volume (medium filling cystometry 180 +/- 100 ml. and ambulatory monitoring 179 +/- 88 ml., p not significant). However, the peak urinary flow rate at the end of medium filling cystometry (4 +/- 6 ml. per second) was significantly lower than during ambulatory monitoring (9 +/- 4 ml. per second, p less than 0.05). The bladder contraction pressure during medium filling cystometry (79 +/- 44 cm. water) was significantly lower than during ambulatory monitoring (107 +/- 39 cm. water, p less than 0.005). Bladder pressures during voiding recorded after natural filling were significantly greater than after artificial filling. This finding may have significant implications for the use of conventional cystometry to study conditions such as outflow obstruction.


Multifaceted roles of GSK-3 and Wnt/β-catenin in hematopoiesis and leukemogenesis: opportunities for therapeutic intervention.
Glycogen synthase kinase-3 (GSK-3) is well documented to participate in a complex array of critical cellular processes. It was initially identified in rat skeletal muscle as a serine/threonine kinase that phosphorylated and inactivated glycogen synthase. This versatile protein is involved in numerous signaling pathways that influence metabolism, embryogenesis, differentiation, migration, cell cycle progression and survival. Recently, GSK-3 has been implicated in leukemia stem cell pathophysiology and may be an appropriate target for its eradication. In this review, we will discuss the roles that GSK-3 plays in hematopoiesis and leukemogenesis as how this pivotal kinase can interact with multiple signaling pathways such as: Wnt/β-catenin, phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/Akt/mammalian target of rapamycin (mTOR), Ras/Raf/MEK/extracellular signal-regulated kinase (ERK), Notch and others. Moreover, we will discuss how targeting GSK-3 and these other pathways can improve leukemia therapy and may overcome therapeutic resistance. In summary, GSK-3 is a crucial regulatory kinase interacting with multiple pathways to control various physiological processes, as well as leukemia stem cells, leukemia progression and therapeutic resistance. GSK-3 and Wnt are clearly intriguing therapeutic targets.


Relationship between Pesticide Metabolites, Cytokine Patterns, and Asthma-Related Outcomes in Rural Women Workers.
The objective of this study was to investigate the relationship between exposure to organophosphate (OP) and pyrethroid (PYR) pesticides with serum cytokine patterns and asthma-related outcomes among rural women workers. A cross-sectional study was conducted among rural women (n = 211), including those working and living on farms and nearby town dwellers. Pesticide exposure was assessed using urinary metabolite concentrations of OP and PYR pesticides. Health outcome assessment was ascertained through the European Community Respiratory Health Survey (ECRHS) questionnaire, fractional exhaled nitric oxide (FeNO), and serum cytokines associated with asthma. The prevalence of doctor-diagnosed asthma was 11%, adult-onset asthma 9%, and current asthma 6%. In this population, the proportion of T helper type 2 (Th2) cytokines (interleukin (IL)-4, IL-5, and IL-13) detectable in subjects was between 18% and 40%, while the proportion of non-Th2 cytokines (IL-6, IL-8, IL-10, IL-17, and interferon gamma) was between 35% and 71%. Most Th2 and non-Th2 cytokines were positively associated with either OP or PYR metabolites. Non-Th2 cytokines showed much stronger associations with OP metabolites (Dimethyl phosphate OR = 4.23; 95% CI: 1.54-11.65) than Th2 cytokines (Dimethyl phosphate OR = 1.69; 95% CI: 0.83-3.46). This study suggests that exposure to most OP and some PYR pesticides may be associated with asthma-related cytokines, with non-Th2 cytokines demonstrating consistently stronger relationships.


Hidradenitis suppurativa, introduction.
Hidradenitis suppurativa (HS) is a prevalent and devastating inflammatory skin disease predominating in women and minorities. HS is characterized by painful recurrent abscesses, foul-smelling purulent drainage, sinus tract and fistula formation, and disfiguring scarring involving intertriginous body sites including the axillae, breasts, groin, and buttocks. Disease onset typically occurs in the second to fourth decades of life and is associated with significant impacts on physical and psychological well-being due to pain, shame, and isolation, leading to profound suffering and despair. HS is both clinically and biologically understudied and therefore poorly understood. As a result, no uniformly effective therapies exist for management, and until recently, there was a paucity of high-level evidence to support current treatments.


Electromagnetic interference of external pacemakers by walkie-talkies and digital cellular phones: experimental study.
A number of experimental and clinical studies have documented the risk potential of interference with implanted pacemakers by various types of cellular phones. Radiofrequency susceptibility of external medical equipment has also been reported in experimental studies. The purpose of this experimental study was to evaluate electromagnetic interference of external pacemakers by walkie-talkies and digital cellular telephones. External bipolar pacing was monitored using a digital oscilloscope to record pacemaker pulses and electromagnetic interference separately. Tests with the walkie-talkie, Private Mobile Radio (PMR) (160 MHz, 2.5 W) were conducted during the calling phase. Tests with the cellular phones, global system for mobile communications (GSM) (900 MHz, 2 W) and Digital Cellular System (DCS) (1,800 MHz, 1 W) were conducted in the test mode. Nine widely used external pacemakers from four manufacturers were tested. Various disturbances including pacing inhibition and asynchronous pacing were observed in eight pacemakers by the PMR, in four by the GSM phone, and in two by the DCS phone. The maximum distance that interference persisted ranged from 10-200 cm. This experimental study shows a potential risk of interference of external pacemakers by walkie-talkies and cellular digital phones. Appropriate warnings should be issued against the potentially serious risks of using communication devices in the vicinity of acutely ill patients treated with temporary transvenous cardiac pacemakers.


The molecular mechanisms of antimetastatic ruthenium compounds explored through DIGE proteomics.
DIGE (difference in gel electrophoresis) proteomics is exploited here to gain insight into the molecular mechanisms of two established ruthenium-based antimetastatic agents, namely trans-[tetrachloro (DMSO) (imidazole)ruthenate(III)] (NAMI-A) and [Ru(η(6)-toluene)Cl(2)(PTA)] (RAPTA-T), where PTA is 1,3,5-triaza-7-phosphaadamantane. Following 24h exposure of A2780/S human ovarian carcinoma cells to pharmacologically relevant concentrations of either ruthenium compound, 2D-DIGE proteomic analysis evidenced only few differentially expressed proteins with respect to controls. Successive mass spectrometry measurements, MALDI-TOF (matrix assisted laser desorption ionization-time of flight) or LC-ESI/MS-MS (liquid chromatography-electrospray ionization/multi-stage mass spectrometry), allowed identification of most altered protein spots, some of which were associated to perturbations in specific cellular functions. Direct insight into the cellular effects of the investigated metallodrugs is thus achieved. Notably, the patterns of protein alterations induced by NAMI-A and RAPTA-T are quite similar to each other while being deeply different from those of cisplatin. To the best of our knowledge this is the first proteomic study on human cancer cells investigating responses to antimetastatic ruthenium drugs. The key role of new "omic" approaches for deciphering the elusive and complex biochemical mechanisms through which anticancer metallodrugs produce their pharmacological effects is further documented.


Key Role of the Ocean Western Boundary currents in shaping the Northern Hemisphere climate.
The individual impact of North Atlantic and Pacific Ocean Western Boundary Currents (OWBCs) on the tropospheric circulation has recently been studied in depth. However, their simultaneous role in shaping the hemisphere-scale wintertime troposphere/stratosphere-coupled circulation and its variability have not been considered. Through semi-idealized Atmospheric General-Circulation-Model experiments, we show that the North Atlantic and Pacific OWBCs jointly maintain and shape the wintertime hemispheric circulation and its leading mode of variability Northern Annular Mode (NAM). The OWBCs energize baroclinic waves that reinforce quasi-annular hemispheric structure in the tropospheric eddy-driven jetstreams and NAM variability. Without the OWBCs, the wintertime NAM variability is much weaker and its impact on the continental and maritime surface climate is largely insignificant. Atmospheric energy redistribution caused by the OWBCs acts to damp the near-surface atmospheric baroclinicity and compensates the associated oceanic meridional energy transport. Furthermore, the OWBCs substantially weaken the wintertime stratospheric polar vortex by enhancing the upward planetary wave propagation, and thereby affecting both stratospheric and tropospheric NAM-annularity. Whereas the overall impact of the extra-tropical OWBCs on the stratosphere results mainly from the Pacific, the impact on the troposphere results from both the Pacific and Atlantic OWBCs.


Zinc is a determinant of the cytotoxicity of Ziram, a dithiocarbamate fungicide, in rat thymic lymphocytes: possible environmental risks.
Ziram, one of the dithiocarbamate fungicides, is widely applied to agriculture because this agent protects various crops from fungal infections. Risks of dithiocarbamate biocide use are of concern. It was previously reported that Ziram increased the intracellular concentration of Zn2+. Therefore, we cytometrically studied the mechanism of Zn2+-dependent lethal actions of Ziram on rat lymphocytes at environmentally relevant Zn2+ levels. Membrane and cellular parameters of rat lymphocytes were estimated by flow-cytometric techniques with appropriate fluorescent probes. The Ziram-induced increase in cell lethality was completely attenuated by Zn2+ chelators. A significant increase of cell lethality was found on the simultaneous application of Ziram at a sublethal concentration and ZnCl2. The combination of Ziram and ZnCl2 increased the cellular superoxide anion content and decreased the cellular GSH content, which possibly caused the increase in cell lethality. The zinc concentrations under the present experimental conditions were comparable to the environmentally relevant concentrations found in rivers. Therefore, the environmental level of zinc may be critical in estimating the toxicity of Ziram to wild animals.


A globally coherent fingerprint of climate change impacts across natural systems.
Causal attribution of recent biological trends to climate change is complicated because non-climatic influences dominate local, short-term biological changes. Any underlying signal from climate change is likely to be revealed by analyses that seek systematic trends across diverse species and geographic regions; however, debates within the Intergovernmental Panel on Climate Change (IPCC) reveal several definitions of a 'systematic trend'. Here, we explore these differences, apply diverse analyses to more than 1,700 species, and show that recent biological trends match climate change predictions. Global meta-analyses documented significant range shifts averaging 6.1 km per decade towards the poles (or metres per decade upward), and significant mean advancement of spring events by 2.3 days per decade. We define a diagnostic fingerprint of temporal and spatial 'sign-switching' responses uniquely predicted by twentieth century climate trends. Among appropriate long-term/large-scale/multi-species data sets, this diagnostic fingerprint was found for 279 species. This suite of analyses generates 'very high confidence' (as laid down by the IPCC) that climate change is already affecting living systems.


Toxicogenomics directory of chemically exposed human hepatocytes.
A long-term goal of numerous research projects is to identify biomarkers for in vitro systems predicting toxicity in vivo. Often, transcriptomics data are used to identify candidates for further evaluation. However, a systematic directory summarizing key features of chemically influenced genes in human hepatocytes is not yet available. To bridge this gap, we used the Open TG-GATES database with Affymetrix files of cultivated human hepatocytes incubated with chemicals, further sets of gene array data with hepatocytes from human donors generated in this study, and publicly available genome-wide datasets of human liver tissue from patients with non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular cancer (HCC). After a curation procedure, expression data of 143 chemicals were included into a comprehensive biostatistical analysis. The results are summarized in the publicly available toxicotranscriptomics directory ( http://wiki.toxbank.net/toxicogenomics-map/ ) which provides information for all genes whether they are up- or downregulated by chemicals and, if yes, by which compounds. The directory also informs about the following key features of chemically influenced genes: (1) Stereotypical stress response. When chemicals induce strong expression alterations, this usually includes a complex but highly reproducible pattern named 'stereotypical response.' On the other hand, more specific expression responses exist that are induced only by individual compounds or small numbers of compounds. The directory differentiates if the gene is part of the stereotypical stress response or if it represents a more specific reaction. (2) Liver disease-associated genes. Approximately 20 % of the genes influenced by chemicals are up- or downregulated, also in liver disease. Liver disease genes deregulated in cirrhosis, HCC, and NASH that overlap with genes of the aforementioned stereotypical chemical stress response include CYP3A7, normally expressed in fetal liver; the phase II metabolizing enzyme SULT1C2; ALDH8A1, known to generate the ligand of RXR, one of the master regulators of gene expression in the liver; and several genes involved in normal liver functions: CPS1, PCK1, SLC2A2, CYP8B1, CYP4A11, ABCA8, and ADH4. (3) Unstable baseline genes. The process of isolating and the cultivation of hepatocytes was sufficient to induce some stress leading to alterations in the expression of genes, the so-called unstable baseline genes. (4) Biological function. Although more than 2,000 genes are transcriptionally influenced by chemicals, they can be assigned to a relatively small group of biological functions, including energy and lipid metabolism, inflammation and immune response, protein modification, endogenous and xenobiotic metabolism, cytoskeletal organization, stress response, and DNA repair. In conclusion, the introduced toxicotranscriptomics directory offers a basis for a rationale choice of candidate genes for biomarker evaluation studies and represents an easy to use source of background information on chemically influenced genes.


Motor neuronal protection by L-arginine prolongs survival of mutant SOD1 (G93A) ALS mice.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive paralysis due to motor neuron degeneration. Despite the fact that many different therapeutic strategies have been applied to prevent disease progression, no cure or effective therapy is currently available for ALS. We found that L-arginine protects cultured motor neurons from excitotoxic injury. We also found that L-arginine supplementation both prior to and after the onset of motor neuron degeneration in mtSOD1 (G93A) transgenic ALS mice significantly slowed the progression of neuropathology in lumbar spinal cord, delayed onset of motor dysfunction, and prolonged life span. Moreover, L-arginine treatment was associated with preservation of arginase I activity and neuroprotective polyamines in spinal cord motor neurons. Our findings show that L-arginine has potent in vitro and in vivo neuroprotective properties and may be a candidate for therapeutic trials in ALS.


Genetic Isolation of Hypothalamic Neurons that Regulate Context-Specific Male Social Behavior.
Nearly all animals engage in a complex assortment of social behaviors that are essential for the survival of the species. In mammals, these behaviors are regulated by sub-nuclei within the hypothalamus, but the specific cell types within these nuclei responsible for coordinating behavior in distinct contexts are only beginning to be resolved. Here, we identify a population of neurons in the ventral premammillary nucleus of the hypothalamus (PMV) that are strongly activated in male intruder mice in response to a larger resident male but that are not responsive to females. Using a combination of molecular and genetic approaches, we demonstrate that these PMV neurons regulate intruder-specific male social behavior and social novelty recognition in a manner dependent on synaptic release of the excitatory neurotransmitter glutamate. These data provide direct evidence for a unique population of neurons that regulate social behaviors in specific contexts.


TNF-alpha production by eosinophils in upper airways inflammation (nasal polyposis).
TNF-alpha is a cytokine with a wide spectrum of proinflammatory activities. Nasal polyps (NP), which occur in association with allergic rhinitis and asthma, are characterized by a marked infiltration of activated eosinophils, epithelial damage, and varying degrees of stromal fibrosis. By using Southern blot analysis after a reverse transcription-PCR, we detected a signal specific for TNF-alpha mRNA in five of seven NP samples, but not in control nasal mucosal samples. With in situ hybridization, we detected cells expressing mRNA specific for TNF-alpha in eight of thirteen NP samples, but not in four control samples. Counterstaining with chromotrope 2R demonstrated that virtually all cells expressing TNF-alpha message were eosinophils. The ratio of eosinophils expressing TNF-alpha to the total number of eosinophils varied greatly among tissues; as an average, we observed 24% TNF-alpha-positive eosinophils. Using a mAb against human TNF-alpha, we demonstrated TNF-alpha localization in 12 NP tissues (48.8 +/- 16.5 positive cells/mm2) but not in three control samples. Morphologically, cells localizing TNF-alpha were both mononucleated and polynucleated with only a small number of eosinophils, as determined by aniline blue counterstaining. Studies of purified blood eosinophils from a patient with hypereosinophilic syndrome and from four healthy donors indicated that TNF-alpha is produced, but rapidly secreted, so that TNF-alpha mRNA-positive cells contain little detectable protein. Furthermore, cells that retain detectable TNF-alpha may not contain sufficient TNF-alpha mRNA to be detected by using the probe developed for our studies. Together, these findings identify a novel mechanism by which eosinophils may contribute to mucosal inflammation and provide an approach to future investigation.


Inhibition of androgen receptor signaling by selenite and methylseleninic acid in prostate cancer cells: two distinct mechanisms of action.
The development of prostate cancer and its progression to a hormone-refractory state is highly dependent on androgen receptor (AR) expression. Recent studies have shown that the selenium-based compound methylseleninic acid (MSeA) can disrupt AR signaling in prostate cancer cells. We have found that selenite can inhibit AR expression and activity in LAPC-4 and LNCaP prostate cancer cells as well but through a different mechanism. On entering the cell, selenite consumes reduced glutathione (GSH) and generates superoxide radicals. Pretreatment with N-acetylcysteine, a GSH precursor, blocked the down-regulation of AR mRNA and protein expression by selenite and restored AR ligand binding and prostate-specific antigen expression to control levels. MSeA reacts with reduced GSH within the cell; however, N-acetylcysteine did not effect MSeA-induced down-regulation of AR and prostate-specific antigen. The superoxide dismutase mimetic MnTMPyP was also found to prevent the decrease in AR expression caused by selenite but not by MSeA. A Sp1-binding site in the AR promoter is a key regulatory component for its expression. Selenite decreased Sp1 expression and activity, whereas MSeA did not. The inhibition of Sp1 by selenite was reversed in the presence of N-acetylcysteine. In conclusion, we have found that selenite and MSeA disrupt AR signaling by distinct mechanisms. The inhibition of AR expression and activity by selenite occurs via a redox mechanism involving GSH, superoxide, and Sp1.


An activated Th17-prone T cell subset involved in chronic graft-versus-host disease sensitive to pharmacological inhibition.
Chronic graft-versus-host disease (cGvHD) remains a major complication of allogeneic stem cell transplantation requiring novel therapies. CD146 and CCR5 are expressed by activated T cells and associated with increased T cell migration capacity and Th17 polarization. We performed a multiparametric flow cytometry analysis in a cohort of 40 HSCT patients together with a cGvHD murine model to understand the role of CD146-expressing subsets. We observed an increased frequency of CD146+ CD4 T cells in the 20 patients with active cGvHD with enhanced RORγt expression. This Th17-prone subset was enriched for cells coexpressing CD146 and CCR5 that harbor mixed Th1/Th17 features and were more frequent in cGvHD patients. Utilizing a murine cGvHD model with bronchiolitis obliterans (BO), we observed that donor T cells from CD146-deficient mice versus those from WT mice caused significantly reduced pulmonary cGvHD. Reduced cGvHD was not the result of failed germinal center B cell or T follicular helper cell generation. Instead, CD146-deficient T cells had significantly lower pulmonary macrophage infiltration and T cell CCR5, IL-17, and IFN-γ coexpression, suggesting defective pulmonary end-organ effector mechanisms. We, thus, evaluated the effect of TMP778, a small-molecule RORγt activity inhibitor. TMP778 markedly alleviated cGvHD in murine models similarly to agents targeting the Th17 pathway, such as STAT3 inhibitor or IL-17-blocking antibody. Our data suggest CD146-expressing T cells as a cGvHD biomarker and suggest that targeting the Th17 pathway may represent a promising therapy for cGvHD.


A model of NEFA dynamics with focus on the postprandial state.
To improve the understanding of the mechanisms underlying the behavior of plasma non-esterified fatty acids (NEFA) in the postprandial state, we have developed a physiology-based mathematical model of plasma NEFA dynamics. Known physiological mechanisms are quantified and used to describe NEFA dynamics. Insulin is the major regulator of NEFA metabolism in the postprandial state. Plasma NEFA levels are thus highly dependent on the insulin concentration, the insulin sensitivity of adipose tissue, and the maximal lipolytic rate. In the postabsorptive state, e.g., at low insulin, adipose tissue lipolysis results in a net export of NEFA from adipose tissue to other tissues. Postprandially, the rise in insulin results in: Decreased lipolysis; a higher rate of lipoprotein lipase (LPL) activity; and decreased NEFA uptake and reesterification by adipose tissue stimulation of reesterification. The result is a drop in plasma NEFA after a carbohydrate containing meal. When insulin returns to postabsorptive levels, a rebound in plasma NEFA often occurs. This rebound is due to a restoration of lipolysis, a decrease in NEFA reesterification by adipose tissue and an increased LPL-as insulin activates LPL with a delay of several hours. In conclusion, movements of NEFA depend strongly on insulin-with postprandial plasma NEFA being almost inversely related to the insulin concentration in healthy humans. The model provides an integrative view of NEFA dynamics and a framework for quantitative and conceptual understanding of plasma NEFA fluxes.


The role of mycobacteria and the effect of proteolytic degradation of thyroglobulin on the production of autoimmune thyroiditis.
Data are presented which suggest that the initial event involved in experimental autoimmune thyroiditis following injection of rabbits with homologous thyroglobulin in complete Freund's adjuvant is alteration of the thyroglobulin. Alteration of the thyroglobulin does not occur during incorporation into the adjuvant or in vitro storage in the adjuvant, and the mycobacteria in the adjuvant have no direct effect on the thyroglobulin. Most likely, the alteration results from an increase in hydrogen ion concentration within cells or local areas in the granuloma and the subsequent action of proteolytic enzymes. These conditions are probably established in the granuloma as the result of neutrophilic response to the mycobacteria in the adjuvant. Rabbits injected with aqueous preparations of homologous thyroglobulin partially degraded in vitro with pepsin at acid pH produced antibody to native thyroglobulin and developed thyroiditis. Most of these rabbits responded to a subsequent injection of native thyroglobulin given 1 month later.


Tube bundle system studies at Signal Peak Energy Bull Mountains #1 Mine.
A tube bundle system (TBS) is a mechanical system for continuously drawing gas samples through tubes from multiple monitoring points located in an underground coal mine for analysis and display on the surface. The U.S. National Institute for Occupational Safety and Health (NIOSH), in collaboration with Signal Peak Energy (SPE), LLC, Bull Mountains No. 1 Mine, operated a TBS during mining of two bleederless, longwall panels. This paper describes the gas analysis data and its interpretation. As verified by the TBS, coal at the SPE mine tends to oxidize slowly. It was known that a reservoir of low-oxygen concentration atmosphere developed about 610 m (2,000 ft) behind the longwall face. A bleederless ventilation system facilitates formation of an inert atmosphere in this longwall gob and decreases the likelihood of spontaneous combustion. Connections of the mine atmosphere to the surface through subsidence cracks could allow airflow into the longwall gob, revive coal oxidation and increase spontaneous combustion risk. The atmospheric composition of the sealed areas was homogeneous, except in the immediate vicinity of suspected ingassing points. The TBS verified that gases within the partially sealed, bleederless longwall gob expanded into the longwall tailgate area when barometric pressure decreased. The concentration of carbon dioxide in the back return airflow at the longwall tailgate was observed to increase by a factor of three and possibly up to 10 times the typical background concentration of 0.5 to 1.0%, depending on the size of the longwall gob and the magnitude of barometric pressure decrease. TBS have the inherent disadvantage of slow response time due to travel time of the gas samples and sequential gas analyses. A TBS or similar continuous monitoring system could be beneficial in detecting and providing warning of potentially hazardous gas concentrations, if the slow response time of the system is always understood.


Autonomous expression of tissue-specific genes in dissociated sea urchin embryos.
The effects of disrupting cell interactions in early development were investigated by examining the accumulation of a primary mesenchyme specific transcript (SM50) and an aboral ectoderm-specific transcript (Spec 1) in cultures of sea urchin embryos that were dissociated at early stages and then cultured in CFSW. The expression of both SM50 and Spec 1 is temporally correct and remains restricted to the appropriate cell types, even if the embryo is dissociated as early as the 2-cell stage and maintained as a suspension of single cells. This result is consistent with the idea that the specificity of expression of these two genes, each characteristic of different lineages, is strongly regulated by information in the egg. Average SM50 expression is half that of intact embryos, but Spec 1 expression is very low, only 10-20% of intact controls, suggesting some differences in the response of the two genes to lack of close cell interactions.


Objectively recorded physical activity in pregnancy and postpartum in a multi-ethnic cohort: association with access to recreational areas in the neighbourhood.
Physical activity may reduce the risk of adverse pregnancy outcomes; however, compared to non-pregnant women, a lower proportion of pregnant women meet the physical activity guidelines. Our objectives were to explore overall changes and ethnic differences in objectively recorded moderate-to-vigorous intensity physical activity (MVPA) during pregnancy and postpartum and to investigate the associations with objective and perceived access to recreational areas. We analysed 1,467 person-observations from 709 women in a multi-ethnic population-based cohort, with MVPA data recorded with the SenseWear™ Pro(3) Armband in early pregnancy (mean gestational week (GW) 15), mid-pregnancy (mean GW 28) and postpartum (mean postpartum week 14). MVPA was limited to bouts ≥10 min. Women were nested within 56 neighbourhoods defined by postal code area. We derived neighbourhood-level objective access to recreational areas (good vs limited) by geographic information systems. We collected information about perceived access (high vs low perception) to recreational areas in early pregnancy. We treated ethnicity, objective and perceived access as explanatory variables in separate models based on linear mixed effects regression analyses. Overall, MVPA dropped between early and mid-pregnancy, followed by an increase postpartum. Western women performed more MVPA than women in other ethnic groups across time points, but the differences increased postpartum. Women residing in neighbourhoods with good objective access to recreational areas accumulated on average nine additional MVPA minutes/day (p < 0.01) compared with women in neighbourhoods with limited access. Women with perceptions of high access to recreational areas accumulated on average five additional MVPA minutes/day (p < 0.01) compared with women with perceptions of low access. After mutual adjustments, perceived and objective access to recreational areas remained significantly associated with MVPA. The association between MVPA and access to recreational areas did not differ by time point, ethnic group or socio-economic position. In all ethnic groups, we observed a decline in MVPA between early and mid-pregnancy. However, at both time points during pregnancy, and especially three months postpartum, Western women were more physically active than ethnic minority women. In all ethnic groups, and at all three time points, both objective and perceived access to recreational areas were positively associated with MVPA levels.


Shale gas development impacts on surface water quality in Pennsylvania.
Concern has been raised in the scientific literature about the environmental implications of extracting natural gas from deep shale formations, and published studies suggest that shale gas development may affect local groundwater quality. The potential for surface water quality degradation has been discussed in prior work, although no empirical analysis of this issue has been published. The potential for large-scale surface water quality degradation has affected regulatory approaches to shale gas development in some US states, despite the dearth of evidence. This paper conducts a large-scale examination of the extent to which shale gas development activities affect surface water quality. Focusing on the Marcellus Shale in Pennsylvania, we estimate the effect of shale gas wells and the release of treated shale gas waste by permitted treatment facilities on observed downstream concentrations of chloride (Cl(-)) and total suspended solids (TSS), controlling for other factors. Results suggest that (i) the treatment of shale gas waste by treatment plants in a watershed raises downstream Cl(-) concentrations but not TSS concentrations, and (ii) the presence of shale gas wells in a watershed raises downstream TSS concentrations but not Cl(-) concentrations. These results can inform future voluntary measures taken by shale gas operators and policy approaches taken by regulators to protect surface water quality as the scale of this economically important activity increases.


Immediate versus conventional loading with fixed full-arch prostheses in mandibles with failing dentition: a prospective controlled study.
To compare immediate and conventional loading protocols for fixed full-arch mandibular prostheses supported by immediate and nonimmediate implants. A prospective controlled nonrandomized study with 12 months of follow-up included patients requiring fixed full-arch rehabilitations supported by immediate and nonimmediate implants. Eighteen patients were treated with conventional loading (control group), and 18 were treated with immediate loading (test group). Each patient received four to six implants; implants with insertion torque < 35 Ncm were excluded from the study and loaded conventionally. The following variables were assessed: implant success, biologic and prosthetic complications, success of the immediately loaded provisional prostheses, and marginal bone loss. Statistical analysis was performed with nonparametric tests (chi-square, Mann-Whitney, Kruskal-Wallis) with an alpha value of .05. Thirty-six patients consecutively enrolled in the study. Two control group patients failing to attend control visits and 12 implants that did not achieve an insertion torque of 35 Ncm were excluded. The final sample consisted of 34 patients and 183 implants (98 test and 85 control implants). Implant success rates were 99.0% (test) and 97.6% (control). Within the test group, success rates for immediate and nonimmediate implants were 100% and 97.6%, respectively. Differences were not statistically significant. All immediately loaded prostheses were successful. Five provisional fixed prostheses presented with loosened screws; all control group patients reported discomfort with the provisional denture. Average bone loss was 0.71 mm (standard deviation 0.25 mm) in the test group and 0.60 mm (standard deviation 0.28 mm) in the control group. No significant differences were seen in implant success and peri-implant marginal bone loss between immediate and conventional loading of mandibular fixed full-arch prostheses supported by immediate and nonimmediate implants. Biologic and prosthetic complications were rare, and all immediately loaded provisional fixed prostheses performed successfully.


Patterns of maxillofacial injuries in powered watercraft collisions.
Because of the widespread popularity of water sports, plastic and reconstructive surgeons can expect to manage an increasing number of injuries associated with these activities, particularly those related to powered watercraft vehicles. Although seat belts for motorists and helmets for motorcyclists may be efficacious, such devices currently do not serve a similar role in powered watercraft sports. In this study, a retrospective chart review of 194 consecutive patients who presented to the University of Miami/Jackson Memorial Hospital (Level I trauma center) as a result of powered watercraft collisions is presented. The purpose of this investigation was to assess the incidence, cause, demographics, and available management options for head and neck injuries secondary to powered watercraft. Identified were 194 patients who presented because of watersports-related injuries during the period January 1, 1991, through December 31, 1996. From this group, 81 patients (41.8 percent) sustained injuries directly attributable to powered watercraft collisions, including 41 personal watercraft collisions (50.6 percent), 39 boat collisions (48.1 percent), and 1 airboat collision (1.2 percent). The patient population, as expected, tended to be young and male with an average age of 29 years (range, 8 to 64 years old). Interestingly, 41 of the patients (50.6 percent) who presented to this trauma center as a result of powered watercraft collisions also sustained associated head and neck trauma. Of 74 injuries 24 were facial fractures (32.4 percent), 18 were facial lacerations (24.3 percent), 14 were closed head injuries (18.9 percent), 8 were skull fractures (10.8 percent), 4 were scalp lacerations (5.4 percent), 4 were C-spine fractures (5.4 percent), 1 was an ear laceration (1.4 percent), and 1 was a fatality (1.4 percent). Le Fort fractures were the most commonly identified facial fracture in this series. The number of these injuries seen in hospital emergency rooms will most likely increase in the future as the popularity of water-related recreational activities becomes even more widespread. Based on these findings, it is strongly recommended that future efforts be directed toward the prevention of these injuries through patient education and the eventual development of efficacious and safe protective equipment.


A novel pathway involving melanoma differentiation associated gene-7/interleukin-24 mediates nonsteroidal anti-inflammatory drug-induced apoptosis and growth arrest of cancer cells.
Numerous studies show that nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in chemoprevention or treatment of cancer. Nevertheless, the mechanisms underlying these antineoplastic effects remain poorly understood. Here, we report that induction of the cancer-specific proapoptotic cytokine melanoma differentiation associated gene-7/interleukin-24 (MDA-7/IL-24) by several NSAIDs is an essential step for induction of apoptosis and G(2)-M growth arrest in cancer cells in vitro and inhibition of tumor growth in vivo. We also show that MDA-7/IL-24-dependent up-regulation of growth arrest and DNA damage inducible 45 alpha (GADD45alpha) and GADD45gamma gene expression is sufficient for cancer cell apoptosis via c-Jun NH(2)-terminal kinase (JNK) activation and growth arrest induction through inhibition of Cdc2-cyclin B checkpoint kinase. Knockdown of GADD45alpha and GADD45gamma transcription by small interfering RNA abrogates apoptosis and growth arrest induction by the NSAID treatment, blocks JNK activation, and restores Cdc2-cyclin B kinase activity. Our results establish MDA-7/IL-24 and GADD45alpha and GADD45gamma as critical mediators of apoptosis and growth arrest in response to NSAIDs in cancer cells.


Effects of n-3 fatty acids, EPA v. DHA, on depressive symptoms, quality of life, memory and executive function in older adults with mild cognitive impairment: a 6-month randomised controlled trial.
Depressive symptoms may increase the risk of progressing from mild cognitive impairment (MCI) to dementia. Consumption of n-3 PUFA may alleviate both cognitive decline and depression. The aim of the present study was to investigate the benefits of supplementing a diet with n-3 PUFA, DHA and EPA, for depressive symptoms, quality of life (QOL) and cognition in elderly people with MCI. We conducted a 6-month double-blind, randomised controlled trial. A total of fifty people aged >65 years with MCI were allocated to receive a supplement rich in EPA (1·67 g EPA + 0·16 g DHA/d; n 17), DHA (1·55 g DHA + 0·40 g EPA/d; n 18) or the n-6 PUFA linoleic acid (LA; 2·2 g/d; n 15). Treatment allocation was by minimisation based on age, sex and depressive symptoms (Geriatric Depression Scale, GDS). Physiological and cognitive assessments, questionnaires and fatty acid composition of erythrocytes were obtained at baseline and 6 months (completers: n 40; EPA n 13, DHA n 16, LA n 11). Compared with the LA group, GDS scores improved in the EPA (P=0·04) and DHA (P=0·01) groups and verbal fluency (Initial Letter Fluency) in the DHA group (P=0·04). Improved GDS scores were correlated with increased DHA plus EPA (r 0·39, P=0·02). Improved self-reported physical health was associated with increased DHA. There were no treatment effects on other cognitive or QOL parameters. Increased intakes of DHA and EPA benefited mental health in older people with MCI. Increasing n-3 PUFA intakes may reduce depressive symptoms and the risk of progressing to dementia. This needs to be investigated in larger, depressed samples with MCI.


Randomized trial of depression follow-up care by online messaging.
Quality of antidepressant treatment remains disturbingly poor. Rates of medication adherence and follow-up contact are especially low in primary care, where most depression treatment begins. Telephone care management programs can address these gaps, but reliance on live contact makes such programs less available, less timely, and more expensive. Evaluate the feasibility, acceptability, and effectiveness of a depression care management program delivered by online messaging through an electronic medical record. Randomized controlled trial comparing usual primary care treatment to primary care supported by online care management Nine primary care clinics of an integrated health system in Washington state Two hundred and eight patients starting antidepressant treatment for depression. Three online care management contacts with a trained psychiatric nurse. Each contact included a structured assessment (severity of depression, medication adherence, side effects), algorithm-based feedback to the patient and treating physician, and as-needed facilitation of follow-up care. All communication occurred through secure, asynchronous messages within an electronic medical record. An online survey approximately five months after randomization assessed the primary outcome (depression severity according to the Symptom Checklist scale) and satisfaction with care, a secondary outcome. Additional secondary outcomes (antidepressant adherence and use of health services) were assessed using computerized medical records. Patients offered the program had higher rates of antidepressant adherence (81% continued treatment more than 3 months vs. 61%, p = 0.001), lower Symptom Checklist depression scores after 5 months (0.95 vs. 1.17, p = 0.043), and greater satisfaction with depression treatment (53% "very satisfied" vs. 33%, p = 0.004). The trial was conducted in one integrated health care system with a single care management nurse. Results apply only to patients using online messaging. Our findings suggest that organized follow-up care for depression can be delivered effectively and efficiently through online messaging.


Zinc deficiency in murine milk underlies expression of the lethal milk (lm) mutation.
The inability of nursing pups to survive on milk of mice homozygous for the recessive mutation, lethal milk (lm), is correlated with a reduction in zinc levels of both milk and pup carcass. Administration of zinc to pups nursing on lmlm dams reduces the observed mortality and morbidity. It is suggested that lm alters zinc transport from maternal blood to milk and that its study may provide useful information for understanding the rare human disease, acrodermatitis enteropathica.


Photoelectron imaging following 2 + 1 multiphoton excitation of HBr.
The photodissociation and photoionization dynamics of HBr via low-n Rydberg and ion-pair states was studied by using 2 + 1 REMPI spectroscopy and velocity map imaging of photoelectrons. Two-photon excitation at about 9.4-10 eV was used to prepare rotationally selected excited states. Following absorption of the third photon the unperturbed F (1)Delta(2) and i (3)Delta(2) states ionize directly into the ground vibrational state of the molecular ion according to the Franck-Condon principle and upon preservation of the ion core. In case of the V (1)Sigma(+)(0(+)) ion-pair state and the perturbed E (1)Sigma(+)(0(+)), g (3)Sigma(-)(0(+)), and H (1)Sigma(+)(0(+)) Rydberg states the absorption of the third photon additionally results in a long vibrational progression of HBr(+) in the X (2)Pi state as well as formation of electronically excited atomic photofragments. The vibrational excitation of the molecular ion is explained by autoionization of repulsive superexcited states into the ground state of the molecular ion. In contrast to HCl, the perturbed Rydberg states of HBr show strong participation of the direct ionization process, with ionic core preservation.


Pulmonary cavitary lesions may be one of the presenting features in Ig A nephropathy.
Immunoglobulin A (Ig A) nephropathy is the most frequent primary glomerulonephritis. Renal limited disease is the most widespread clinical form of the disease. Pulmonary involvement may also be seen concomitantly and capillaritis with pulmonary hemorrhage is the most frequent pulmonary involvement. In this paper, for the first time in literature, we describe an Ig A nephropathy patient with multiple pulmonary cavities as one of the presenting features of the disease. Also, no other etiology for the cavities was found other than Ig A nephropathy. Herein, possible pathogenesis might be capillaritis or deposition of immune complexes. As a result, it should be kept in mind that pulmonary cavity may be the presenting feature of Ig A nephropathy especially with other frequent signs of the disease.


Lithium ions solvated in helium.
We report on a combined experimental and theoretical study of Li+ ions solvated by up to 50 He atoms. The experiments show clear enhanced abundances associated with HenLi+ clusters where n = 2, 6, 8, and 14. We find that classical methods, e.g. basin-hopping (BH), give results that qualitatively agree with quantum mechanical methods such as path integral Monte Carlo, diffusion Monte Carlo and quantum free energy, regarding both energies and the solvation structures that are formed. The theory identifies particularly stable structures for n = 4, 6 and 8 which line up with some of the most abundant features in the experiments.


Sample size and robust marginal methods for cluster-randomized trials with censored event times.
In cluster-randomized trials, intervention effects are often formulated by specifying marginal models, fitting them under a working independence assumption, and using robust variance estimates to address the association in the responses within clusters. We develop sample size criteria within this framework, with analyses based on semiparametric Cox regression models fitted with event times subject to right censoring. At the design stage, copula models are specified to enable derivation of the asymptotic variance of estimators from a marginal Cox regression model and to compute the number of clusters necessary to satisfy power requirements. Simulation studies demonstrate the validity of the sample size formula in finite samples for a range of cluster sizes, censoring rates, and degrees of within-cluster association among event times. The power and relative efficiency implications of copula misspecification is studied, as well as the effect of within-cluster dependence in the censoring times. Sample size criteria and other design issues are also addressed for the setting where the event status is only ascertained at periodic assessments and times are interval censored.


The Tribology of Explanted Hip Resurfacings Following Early Fracture of the Femur.
A recognized issue related to metal-on-metal hip resurfacings is early fracture of the femur. Most theories regarding the cause of fracture relate to clinical factors but an engineering analysis of failed hip resurfacings has not previously been reported. The objective of this work was to determine the wear volumes and surface roughness values of a cohort of retrieved hip resurfacings which were removed due to early femoral fracture, infection and avascular necrosis (AVN). Nine resurfacing femoral heads were obtained following early fracture of the femur, a further five were retrieved due to infection and AVN. All fourteen were measured for volumetric wear using a co-ordinate measuring machine. Wear rates were then calculated and regions of the articulating surface were divided into "worn" and "unworn". Roughness values in these regions were measured using a non-contacting profilometer. The mean time to fracture was 3.7 months compared with 44.4 months for retrieval due to infection and AVN. Average wear rates in the early fracture heads were 64 times greater than those in the infection and AVN retrievals. Given the high wear rates of the early fracture components, such wear may be linked to an increased risk of femoral neck fracture.


Pathways community care coordination in low birth weight prevention.
The evidence is limited on the effectiveness of home visiting care coordination in addressing poor birth outcome, including low birth weight (LBW). The Community Health Access Project (CHAP) utilizes community health workers (CHWs) to identify women at risk of having poor birth outcomes, connect them to health and social services, and track each identified health or social issue to a measurable completion. CHWs are trained individuals from the same highest risk communities. The CHAP Pathways Model is used to track each maternal health and social service need to resolution and CHWs are paid based upon outcomes. We evaluated the impact of the CHAP Pathways program on LBW in an urban Ohio community. Women participating in CHAP and having a live birth in 2001 through 2004 constituted the intervention group. Using birth certificate records, each CHAP birth was matched through propensity score to a control birth from the same census tract and year. Logistic regression was used to examine the association of CHAP participation with LBW while controlling for risk factors for LBW. We identified 115 CHAP clients and 115 control births. Among the intervention group there were seven LBW births (6.1 %) compared with 15 (13.0 %) among non-CHAP clients. The adjusted odds ratio for LBW was 0.35 (95 % confidence interval, 0.12-0.96) among CHAP clients. This study provides evidence that structured community care coordination coupled with tracking and payment for outcomes may reduce LBW birth among high-risk women.


The role of anti-Galalpha1-3Gal antibodies in acute vascular rejection and accommodation of xenografts.
A major impediment to the transplanting of porcine organs into humans is the susceptibility of porcine organs to acute vascular rejection, which can destroy a vascularized xenograft over a period of hours to days. Acute vascular rejection of porcine-to-primate xenografts is thought to be triggered by binding of xenoreactive antibodies to the graft. We tested whether antibodies, binding to Galalpha1-3Gal epitopes in porcine tissue, initiate this phenomenon. Specific depletion of anti-Galalpha1-3Gal antibodies from the blood of baboons, using extracorporeal perfusion of separated plasma through columns of Sepharose beads covalently linked to the antigenic trisaccharide, Galalpha1-3Galbeta1-4GlcAc, averted the development of acute vascular rejection in porcine organs transgenic for human decay-accelerating factor and CD59. More importantly, after immunodepletion was stopped and Gala1-3Gal antibodies were allowed to return, these same organs continued to function and remained pathologically normal and thus seemed to achieve a state of accommodation. These results demonstrate that anti-Galalpha1-3Gal antibodies cause acute vascular rejection and suggest that depletion of these antibodies leads to accommodation of the donor cardiac xenograft and could supply an important model for additional study.


Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients.
Two hundred and twenty-six patients with inherited C1 inhibitor (C1-INH) deficiency, also known as hereditary angioedema (HAE), have been studied. They belonged to 80 unrelated families, and in 11 of them C1-INH was functionally deficient but antigenically normal (type II HAE). Genetic analysis of type 1 families demonstrated restriction fragment length polymorphisms in 11% and abnormal mRNAs in 25%. In type II families, the site of the mutation appeared to determine the rate of catabolism of the dysfunctional C1-INH and its antigenic plasma levels. Clinical symptoms (subcutaneous and mucous swellings) generally first appeared within the second decade of life. The frequency of symptoms was highly variable from patient to patient, but a few patients remained asymptomatic throughout their lives. Prophylactic treatment with attenuated androgens was administered to 59 patients and was totally effective in 57, without significant side effects. Sixty-seven laryngeal and 15 abdominal attacks were treated with C1-INH plasma concentrate, yielding initial regression of symptoms in 30 to 90 minutes. The acquired deficiency of C1-INH, also known as acquired angioedema, was diagnosed in 9 patients. Eight of them had an autoantibody against C1-INH; the only patient without the autoantibody had associated chronic lymphocytic leukemia. Prophylactic treatment with attenuated androgens was effective in this last patient, while those with the autoantibody against C1-INH benefited from prophylaxis with antifibrinolytic agents. Replacement therapy with C1-INH concentrate was necessary only for patients with autoantibodies and required doses 3 or 4 times higher than those used in HAE.


Serrated colorectal polyps in inflammatory bowel disease.
Serrated colorectal polyps, which, besides hyperplastic polyps, comprise sessile serrated adenomas/polyps and traditional serrated adenomas, are presumptive precursors of at least 20% of sporadic colorectal carcinomas; however, their significance in patients with inflammatory bowel disease is unclear. We retrospectively evaluated 78 serrated polyps, removed over a 14-year period from 6602 inflammatory bowel disease patients undergoing endoscopic surveillance, with respect to morphologic, clinicopathologic, and molecular features, and compared rates of advanced neoplasia (high-grade dysplasia and carcinoma) development following the index serrated polyp diagnosis to reference inflammatory bowel disease cohorts without serrated polyps. Serrated polyps negative for dysplasia, which morphologically resembled sporadic sessile serrated adenoma/polyps, occurred mainly in females, in the proximal colon, and contained BRAF mutations. Serrated polyps with low-grade dysplasia resembled sporadic traditional serrated adenomas and occurred mainly in males, in the distal colon, and contained KRAS mutations. Serrated polyps indefinite for dysplasia were morphologically heterogeneous, but similar to serrated polyps positive for low-grade dysplasia with respect to male predominance, left-sided location, and KRAS mutation rates. Rates of prevalent neoplasia associated with serrated polyps positive for low-grade dysplasia, indefinite for dysplasia, and negative for dysplasia were 76, 39, and 11%, respectively (P<0.001). Actuarial 10-year rates of incident advanced neoplasia after an initial diagnosis of serrated polyp positive for low-grade dysplasia, indefinite for dysplasia, and negative for dysplasia were 17, 8, and 0%, respectively, the first and last being significantly different (P=0.02) and comparable to those of corresponding reference populations of inflammatory bowel disease patients with and without low-grade dysplasia at baseline, respectively. We conclude that in serrated polyps from inflammatory bowel disease patients, dysplasia grade correlates with morphology, sex, anatomic location, BRAF and KRAS mutation status, prevalent conventional neoplasia, and rates of advanced neoplasia development.