Characteristics of referrals to an inpatient hospice and a survey of general practitioner perceptions of palliative care.
In order to determine symptoms, drug prescribing and physical problems of patients referred to an inpatient hospice, case notes from 130 consecutive first admissions (95 general practitioner (GP) referrals, 35 consultant referrals) were analysed. GP referrals were more likely to be constipated, require care and be discharged to home. Consultant referrals were more gravely ill, dependent and more likely to die in the hospice. On admission 76 (58%) patients were receiving opiates with co-prescription of opiate and laxative occurring in 41% (31/76) of the cases. The prescription of laxatives with the symptoms of constipation occurred in 62% (26/42) of the cases on admission. A telephone survey of 79 referring GPs revealed that 37% had attended neither a course nor a lecture relevant to palliative care in the past 3 years. GPs experienced difficulties frequently or always in: (a) managing pain (8/79); (b) managing other symptoms (25/79); (c) helping patients and relatives cope with their emotional distress (18/79); and (d) coping with their own emotional responses to death and dying (5/79). In conclusion, the differences demonstrated between the GP and consultant referrals have implications for purchasers. The high incidence of possible opiate-induced side-effects and the difficulties with symptom control expressed by some GPs indicate a continuing need for effective educational input.


Family study of the major histocompatibility complex in patients with systemic lupus erythematosus: importance of null alleles of C4A and C4B in determining disease susceptibility.
The families of 29 patients with systemic lupus erythematosus and 42 normal subjects were studied to determine the inheritance of the HLA-A, B, C, and DR antigens and also the complement polymorphisms for C2, C4A, C4B, and Bf, which are encoded in the same region of the sixth chromosome. Null (silent) alleles for C4A, C4B, or C2 were found in 24 of the 29 (83%) patients compared with 18 of the 42 (43%) normal controls. HLA-DR3 was present in 20 (69%) of the patients and seven out of 39 (18%) of the normal controls. There was strong linkage disequilibrium between DR3 and the null alleles for C4A and C4B. The data did not permit the relative contributions of DR3 and null factors of C4A and C4B as genetic risk factors to be distinguished. The known association of systemic lupus erythematosus with uncommon inherited and acquired deficiencies of complement components suggests, however, that the presence of null alleles for C4A and C4B, as well as C2, found in most of the patients, is relevant to their genetic susceptibility to this disease.


An experimental model of mycobacterial infection under corneal flaps.
In order to develop a new experimental animal model of infection with Mycobacterium chelonae in keratomileusis, we conducted a double-blind prospective study on 24 adult male New Zealand rabbits. One eye of each rabbit was submitted to automatic lamellar keratotomy with the automatic corneal shaper under general anesthesia. Eyes were immunosuppressed by a single local injection of methyl prednisolone. Twelve animals were inoculated into the keratomileusis interface with 1 microl of 10(6) heat-inactivated bacteria (heat-inactivated inoculum controls) and 12 with 1 microl of 10(6) live bacteria. Trimethoprim drops (0.1%, w/v) were used as prophylaxis for the surgical procedure every 4 h (50 microl, qid). Animals were examined by 2 observers under a slit lamp on the 1st, 3rd, 5th, 7th, 11th, 16th, and 23rd postoperative days. Slit lamp photographs were taken to document clinical signs. Animals were sacrificed when corneal disease was detected and corneal samples were taken for microbiological analysis. Eleven of 12 experimental rabbits developed corneal disease, and M. chelonae could be isolated from nine rabbits. Eleven of the 12 controls receiving a heat-inactivated inoculum did not develop corneal disease. M. chelonae was not isolated from any of the control rabbits receiving a heat-inactivated inoculum, or from the healthy cornea of control rabbits. Corneal infection by M. chelonae was successfully induced in rabbits submitted to keratomileusis. To our knowledge, this is the first animal model of M. chelonae infection following corneal flaps for refractive surgery to be described in the literature and can be used for the analysis of therapeutic responses.


Spiritual or religious struggle in hematopoietic cell transplant survivors.
This study describes the prevalence of religious or spiritual (R/S) struggle in long-term survivors after hematopoietic cell transplantation (HCT), demographic and medical correlates of R/S struggle, and its associations with depression and quality of life. Data were collected in conjunction with an annual survey of adult (age ≥18 years) survivors of HCT. Study measures included R/S struggle (negative religious coping, NRC, from Brief RCOPE), measures of quality of life (subscales from 36-item Short Form Health Survey and McGill), and the Patient Health Questionnaire 8. R/S struggle was defined as any non-zero response on the NRC. Factors associated with R/S struggle were identified using multi-variable logistic regression models. The study analyzed data from 1449 respondents who ranged from 6 months to 40 years after HCT. Twenty-seven percent had some R/S struggle. In a multi-variable logistic regression model, R/S struggle was associated with greater depression and poorer quality of life. R/S struggle was also associated with younger age, non-White race, and self-identification as either religious but not spiritual or spiritual but not religious. R/S struggle was not associated with any medical variables, including time since transplant. Religious or spiritual struggle is common among HCT survivors, even many years after HCT. Survivors should be screened and, as indicated, referred to a professional with expertise in R/S struggle. Further study is needed to determine causal relationships, longitudinal trajectory, impact of struggle intensity, and effects of R/S struggle on health, mood, and social roles for HCT survivors. Copyright © 2015 John Wiley & Sons, Ltd.


Suburbanization, estrogen contamination, and sex ratio in wild amphibian populations.
Research on endocrine disruption in frog populations, such as shifts in sex ratios and feminization of males, has predominantly focused on agricultural pesticides. Recent evidence suggests that suburban landscapes harbor amphibian populations exhibiting similar levels of endocrine disruption; however the endocrine disrupting chemical (EDC) sources are unknown. Here, we show that sex ratios of metamorphosing frogs become increasingly female-dominated along a suburbanization gradient. We further show that suburban ponds are frequently contaminated by the classical estrogen estrone and a variety of EDCs produced by plants (phytoestrogens), and that the diversity of organic EDCs is correlated with the extent of developed land use and cultivated lawn and gardens around a pond. Our work also raises the possibility that trace-element contamination associated with human land use around suburban ponds may be contributing to the estrogenic load within suburban freshwaters and constitutes another source of estrogenic exposure for wildlife. These data suggest novel, unexplored pathways of EDC contamination in human-altered environments. In particular, we propose that vegetation changes associated with suburban neighborhoods (e.g., from forests to lawns and ornamental plants) increase the distribution of phytoestrogens in surface waters. The result of frog sex ratios varying as a function of human land use implicates a role for environmental modulation of sexual differentiation in amphibians, which are assumed to only have genetic sex determination. Overall, we show that endocrine disruption is widespread in suburban frog populations and that the causes are likely diverse.


THE EFFECT OF ODOURS, IRRITANT VAPOURS, AND MENTAL WORK UPON THE BLOOD FLOW.
The most important of this investigation has been the completion of various improvements in the construction and use of the plethysmograph, by means of which numerous errors attending the use of the instrument have been eliminated. The results of the work show that all olfactory sensations, so far as they produce any effect through the vasomotor system, tend to diminish the volume of the arm, and therefore presumably cause a congestion of the brain. Whenever the stimulation occassions an increase in the volume of the arm, as sometimes happens, it seems to be due to acceleration of the heart rate, which, of course, tends also to increase the supply of blood to the brain. The of odours varies in extent with different individuals, and with the same individual at different times. It was most marked in subjects sensitive to odours. Irritant vapours, such as formic acid, have a marked effect in the same direction-that is, they cause a strong diminution in the volume of the arm. The experiments give no support to the view that pleasant sensations are accompanied by a diminution of the See PDF for Structure blood supply to the brain and unpleasant sensations by the reverse efeect. In all my experiments mental work caused a marked and prolonged diminution in the volume of the arm. This vasomotor effect was sometimes preceded by a transitory increase in the volume of the arm caused by acceleration of heart rate.


Role of visual and non-visual cues in constructing a rotation-invariant representation of heading in parietal cortex.
As we navigate through the world, eye and head movements add rotational velocity patterns to the retinal image. When such rotations accompany observer translation, the rotational velocity patterns must be discounted to accurately perceive heading. The conventional view holds that this computation requires efference copies of self-generated eye/head movements. Here we demonstrate that the brain implements an alternative solution in which retinal velocity patterns are themselves used to dissociate translations from rotations. These results reveal a novel role for visual cues in achieving a rotation-invariant representation of heading in the macaque ventral intraparietal area. Specifically, we show that the visual system utilizes both local motion parallax cues and global perspective distortions to estimate heading in the presence of rotations. These findings further suggest that the brain is capable of performing complex computations to infer eye movements and discount their sensory consequences based solely on visual cues.


One scaffold, three binding modes: novel and selective pteridine reductase 1 inhibitors derived from fragment hits discovered by virtual screening.
The enzyme pteridine reductase 1 (PTR1) is a potential target for new compounds to treat human African trypanosomiasis. A virtual screening campaign for fragments inhibiting PTR1 was carried out. Two novel chemical series were identified containing aminobenzothiazole and aminobenzimidazole scaffolds, respectively. One of the hits (2-amino-6-chloro-benzimidazole) was subjected to crystal structure analysis and a high resolution crystal structure in complex with PTR1 was obtained, confirming the predicted binding mode. However, the crystal structures of two analogues (2-amino-benzimidazole and 1-(3,4-dichloro-benzyl)-2-amino-benzimidazole) in complex with PTR1 revealed two alternative binding modes. In these complexes, previously unobserved protein movements and water-mediated protein-ligand contacts occurred, which prohibited a correct prediction of the binding modes. On the basis of the alternative binding mode of 1-(3,4-dichloro-benzyl)-2-amino-benzimidazole, derivatives were designed and selective PTR1 inhibitors with low nanomolar potency and favorable physicochemical properties were obtained.


Stimulated saprotrophic fungi in arable soil extend their activity to the rhizosphere and root microbiomes of crop seedlings.
Saprotrophic fungi play an important role in ecosystem functioning and plant performance, but their abundance in intensively managed arable soils is low. Saprotrophic fungal biomass in arable soils can be enhanced with amendments of cellulose-rich materials. Here, we examined if sawdust-stimulated saprotrophic fungi extend their activity to the rhizosphere of crop seedlings and influence the composition and activity of other rhizosphere and root inhabitants. After growing carrot seedlings in sawdust-amended arable soil, we determined fungal and bacterial biomass and community structure in roots, rhizosphere and soil. Utilization of root exudates was assessed by stable isotope probing (SIP) following 13 CO2 -pulse-labelling of seedlings. This was combined with analysis of lipid fatty acids (PLFA/NLFA-SIP) and nucleic acids (DNA-SIP). Sawdust-stimulated Sordariomycetes colonized the seedling's rhizosphere and roots and actively consumed root exudates. This did not reduce the abundance and activity of bacteria, yet higher proportions of α-Proteobacteria and Bacteroidia were seen. Biomass and activity of mycorrhizal fungi increased with sawdust amendments, whereas exudate consumption and root colonization by functional groups containing plant pathogens did not change. Sawdust amendment of arable soil enhanced abundance and exudate-consuming activity of saprotrophic fungi in the rhizosphere of crop seedlings and promoted potential beneficial microbial groups in root-associated microbiomes.


Biobanking informatics infrastructure to support clinical and translational research.
The University of Utah Health Sciences (UUHSC) and Intermountain Healthcare (IH) support high value clinical and translational research programs. The Utah Biohealth Initiative will facilitate next generation research by leveraging the combined resources of both institutions through an infrastructure which links biospecimens and electronic health records (EHR). During phase I of the Utah BioHealth Initiative (UBI) the participating institutions developed a legal, regulatory and information technology infrastructure that supports clinical and translational research, and advances our understanding of health and disease, improves healthcare value and health for current and future generations of Utahns. We used the Federated Utah Research and Translational Health electronic Repository (FURTHeR) 1 to combine EHR and biospecimen data from an actual study populated by both institutions to demonstrate the robustness of the infrastructure.


APRIL:TACI axis is dispensable for the immune response to rabies vaccination.
There is significant need to develop a single-dose rabies vaccine to replace the current multi-dose rabies vaccine regimen and eliminate the requirement for rabies immune globulin in post-exposure settings. To accomplish this goal, rabies virus (RABV)-based vaccines must rapidly activate B cells to secrete antibodies which neutralize pathogenic RABV before it enters the CNS. Increased understanding of how B cells effectively respond to RABV-based vaccines may improve efforts to simplify post-exposure prophylaxis (PEP) regimens. Several studies have successfully employed the TNF family cytokine a proliferation-inducing ligand (APRIL) as a vaccine adjuvant. APRIL binds to the receptors TACI and B cell maturation antigen (BCMA)-expressed by B cells in various stages of maturation-with high affinity. We discovered that RABV-infected primary murine B cells upregulate APRIL ex vivo. Cytokines present at the time of antigen exposure affect the outcome of vaccination by influencing T and B cell activation and GC formation. Therefore, we hypothesized that the presence of APRIL at the time of RABV-based vaccine antigen exposure would support the generation of protective antibodies against RABV glycoprotein (G). In an effort to improve the response to RABV vaccination, we constructed and characterized a live recombinant RABV-based vaccine vector which expresses murine APRIL (rRABV-APRIL). Immunogenicity testing in mice demonstrated that expressing APRIL from the RABV genome does not impact the primary antibody response against RABV G compared to RABV alone. In order to evaluate the necessity of APRIL for the response to rabies vaccination, we compared the responses of APRIL-deficient and wild-type mice to immunization with rRABV. APRIL deficiency does not affect the primary antibody response to vaccination. Furthermore, APRIL expression by the vaccine did not improve the generation of long-lived antibody-secreting plasma cells (PCs) as serum antibody levels were equivalent in response to rRABV-APRIL and the vector eight weeks after immunization. Moreover, APRIL is dispensable for the long-lived antibody-secreting PC response to rRABV vaccination as anti-RABV G IgG levels were similar in APRIL-deficient and wild-type mice six months after vaccination. Mice lacking the APRIL receptor TACI demonstrated primary anti-RABV G antibody responses similar to wild-type mice following immunization with the vaccine vector indicating that this response is independent of TACI-mediated signals. Collectively, our findings demonstrate that APRIL and associated TACI signaling is dispensable for the immune response to RABV-based vaccination.


Development and validation of an index to predict activity of daily living dependence in community-dwelling elders.
Maintaining independence in daily functioning is an important health outcome in older adults. A key measure of functional independence in elders is the ability to do activities of daily living (ADL) without the assistance of another person. However, few prognostic indices have been developed that stratify elders into groups at variable risk for developing ADL dependence. We sought to develop and validate a prognostic index that distinguishes between elders at different risk of ADL dependence. We studied subjects enrolled in Asset and Health Dynamics Among the Oldest Old (AHEAD), a nationally representative cohort of elders older than the age of 70. We included 5239 subjects (mean age, 77) reporting that they could do each of 5 ADL (bathing, dressing, toileting, transferring, and eating) without the assistance of another person at baseline. Subjects were divided into development (n = 3245) and validation (n = 1994) samples based on region of the United States. Our primary outcome was the need for help (dependence) with at least one ADL at 2 years. We used logistic regression to select among predictor variables encompassing several domains: demographic characteristics, comorbid conditions, functional status, cognitive status, and general health indicators. The 9 independent predictors of 2-year ADL dependence were age older than 80, diabetes, difficulty walking several blocks, difficulty bathing or dressing, need for help with personal finances, difficulty lifting 10 pounds, inability to name the Vice President, history of falling, and low body mass index. We created a risk score by assigning 1 point to each risk factor. In the development sample, rates of 2-year ADL dependence in subjects with 0, 1, 2, 3, 4, and 5 or more risk factors were 1.3%, 2.8%, 3.8%, 10%, 22%, and 33%, respectively (P < 0.001, roc area = 0.79). In the validation sample, the rates were 0.7%, 4.3%, 8.7%, 11%, 18%, and 40% (P < 0.001, roc area = 0.77). The risk score also discriminated between subjects at variable risk for a combined outcome of either ADL decline or death (4.3%, 7.6%, 15%, 21%, 30%, and 47%). Using data available from patient reports, we validated a simple risk index that distinguished between elders at variable risk of ADL dependence. This index may be useful for identifying elders at high risk of poor outcomes or for risk adjustment.


Familial Clustering of Type 2 Diabetes among Omanis.
The aim of this study was to screen Omani individuals for the familial aggregation of type 2 diabetes mellitus. A random cohort of 1182 Omani individuals visiting the Family Medicine Clinic at Sultan Qaboos University Hospital (SQUH), Muscat, Oman, for regular medical checkup, aged ≥40 years, were sampled. Patients were categorized into three groups: (1) individuals who claim not to have diabetes and had no family history of diabetes; (2) individuals who claim not to have diabetes but had family history of diabetes; (3) individuals with diabetes. Only 16% of these Omani individuals had no diabetes and no family history of diabetes. Another separate random cohort of 234 Omani type 2 diabetes mellitus patients, from the Diabetes Clinic at SQUH, were interviewed and questioned about their family history of type 2 diabetes mellitus. Ninety five percent of the patients had a family history of diabetes. Eighty percent had first degree relatives with diabetes and 46% had second degree relatives with diabetes. At least one parent with diabetes was reported among 55% of these diabetics, while maternal diabetes (55%) was found to be higher than paternal diabetes (47%). However, only 15% had both parents with diabetes. Furthermore, almost half of the 234 diabetics were having at least one of the following relatives with diabetes: brother, sister, aunt or an uncle. The findings of this study confirm familial aggregation of diabetes among the Omani population. Compared to other populations, familial aggregation of type 2 diabetes mellitus among Omanis is relatively very high, and is perhaps due to the very high degree of consanguinity among Omanis. Since almost everyone seems to have a genetic predisposition to diabetes, the dramatic lifestyle changes over the past 25 years, could tip the population into an epidemic of type 2 diabetes mellitus.


ChSeq: A database of chameleon sequences.
Chameleon sequences (ChSeqs) refer to sequence strings of identical amino acids that can adopt different conformations in protein structures. Researchers have detected and studied ChSeqs to understand the interplay between local and global interactions in protein structure formation. The different secondary structures adopted by one ChSeq challenge sequence-based secondary structure predictors. With increasing numbers of available Protein Data Bank structures, we here identify a large set of ChSeqs ranging from 6 to 10 residues in length. The homologous ChSeqs discovered highlight the structural plasticity involved in biological function. When compared with previous studies, the set of unrelated ChSeqs found represents an about 20-fold increase in the number of detected sequences, as well as an increase in the longest ChSeq length from 8 to 10 residues. We applied secondary structure predictors on our ChSeqs and found that methods based on a sequence profile outperformed methods based on a single sequence. For the unrelated ChSeqs, the evolutionary information provided by the sequence profile typically allows successful prediction of the prevailing secondary structure adopted in each protein family. Our dataset will facilitate future studies of ChSeqs, as well as interpretations of the interplay between local and nonlocal interactions. A user-friendly web interface for this ChSeq database is available at prodata.swmed.edu/chseq.


Rapid adaptation (or not) in restored plant populations.
Mismatches between the traits of a colonizing population and a novel habitat can generate strong selection, potentially resulting in rapid adaptation. However, for most colonization events, it can be difficult to detect rapid adaptation or distinguish it from nonadaptive evolutionary changes. Here, I take advantage of a replicated prairie restoration experiment to compare recently established plant populations in two closely located restored prairies to each other and to their shared source population to test for rapid adaptation. Using a reciprocal transplant experiment six years after the populations were established, I found that one restored plant population showed evidence of adaptation, outperforming the other restored population when grown at its home site. In contrast, I detected no evidence for adaptation at the other site. These findings demonstrate that while rapid adaptation can occur in colonizing plant populations, it may not be the rule. Better understanding of when adaptation may or may not occur in these contexts may help us use evolution to our advantage, potentially improving establishment of desirable species in restored habitats.


Analysis of convergent gene transcripts in the obligate intracellular bacterium Rickettsia prowazekii.
Termination of transcription is an important component of bacterial gene expression. However, little is known concerning this process in the obligate intracellular pathogen and model for reductive evolution, Rickettsia prowazekii. To assess transcriptional termination in this bacterium, transcripts of convergent gene pairs, some containing predicted intrinsic terminators, were analyzed. These analyses revealed that, rather than terminating at a specific site within the intervening region between the convergent genes, most of the transcripts demonstrated either a lack of termination within this region, which generated antisense RNA, or a putative non-site-specific termination that occurred throughout the intervening sequence. Transcripts terminating at predicted intrinsic terminators, as well as at a putative Rho-dependant terminator, were also examined and found to vary based on the rickettsial host environment. These results suggest that transcriptional termination, or lack thereof, plays a role in rickettsial gene regulation.


Effects of training on general practitioners' management of pain in osteoarthritis: a randomized multicenter study.
To evaluate the effects of a short interactive training program for general practitioners (GP) on pain management in patients with osteoarthritis (OA). A multicenter, parallel-group study. GP were randomized to receive training on relationships and communication, pain evaluation, prescription, and negotiation of a patient contract or to a control group receiving a presentation about obtaining consent in trials. Outcomes were patient assessments of pain and functional ability. We invited 1500 GP to take part in the study. Those who volunteered to receive the training recruited outpatients from May 2001 to April 2002. Patients participating in the evaluation of the effects of the general practitioners' training had lower limb OA and pain on motion [> or = 40 mm on a visual analog scale (VAS)] and had indications for treatment with acetaminophen. The primary endpoint: sum of patient pain relief based on the daily VAS self-evaluation during the 2 weeks of the trial. In total, 180 GP (84 trained, 96 nontrained) enrolled 842 patients (414 and 428, respectively). Mean baseline VAS pain was 63 +/- 14 mm. Patients in the trained-GP group had better overall pain relief (316 +/- 290 mm/day vs 265 +/- 243 mm; p < 0.0001), greater improvement in Lequesne and WOMAC scores (p < 0.0001), and better overall perception of treatment (p = 0.002). Acetaminophen use was slightly higher in the trained group; however, the difference in pain relief remained statistically significant (p = 0.0003) after adjustment for this difference. This is the first study to demonstrate a positive effect of physician training on patients with a painful condition.


Performance of the High-dimensional Propensity Score in a Nordic Healthcare Model.
The high-dimensional propensity score (hdPS) is increasingly used as a tool to adjust for confounding in observational studies of drug effects. It was developed within very rich data sources, for example the American claims databases. Thus, it is unknown whether it can be applied in settings that provide little more than primary care prescriptions and diagnoses from hospital contacts, as in the Nordic data sources. Our objective was to evaluate the performance of hdPS under such circumstances. As our case, we chose the association between use of selective cyclooxygenase-2 inhibitors (coxibs) and traditional NSAIDs (tNSAIDs) and the risk of upper GI bleeding. Using Danish health registries, we identified 110,285 incident users of coxibs and 575,980 incident users of tNSAIDs and followed them for 90 days with respect to the occurrence of serious upper GI bleeding. Data were analysed using Cox regression, estimating the coxib/tNSAID hazard ratio (HR). Values below 1.00 indicate a lower estimated hazard with coxibs. We build hdPS models with inclusion of up to 500 diagnosis and 500 prescription drug covariates. The crude HR was 1.76 (95% confidence interval: 1.57-1.97), decreasing to 1.12 (1.00-1.26) and 0.99 (0.88-1.12) after adjustment for age and sex and 11 pre-selected confounders, respectively. A hdPS with inclusion of 500 most prevalent diagnoses and 500 most prevalent prescription drugs resulted in a HR of 0.89 (0.77-1.02). These estimates were consistently lower when the analysis was restricted to non-users of low-dose aspirin. The estimate based on 500 diagnoses alone was higher than an estimate based on 500 prescription drugs alone (0.99 versus 0.91). We conclude that hdPS does work within a Nordic setting that prescription data are more effective than diagnosis data in achieving confounder adjustment and that hdPS seems more effective than simple confounder adjustment by variables selected on the basis of clinical reasoning.


Influence of changes in sedentary behavior on energy and macronutrient intake in youth.
Changes in sedentary behavior may be related to changes in energy intake. The purpose of this study was to investigate how experimental changes in the amount of sedentary behaviors influence energy intake. Sixteen nonoverweight 12-16-y-old youth were studied in a within-subject crossover design with three 3-wk phases: baseline, increasing targeted sedentary behaviors by 25-50% (increase phase), and decreasing targeted sedentary behaviors by 25-50% (decrease phase). Repeated 24-h recalls were used to assess energy and macronutrient intakes during targeted sedentary behaviors. Accelerometers were used to assess activity levels. Targeted sedentary behaviors increased by 81.5 min/d (45.8%) and decreased by 109.8 min/d (-61.2%) from baseline (both: P<0.01). Girls increased sedentary behaviors significantly more than did boys (107.3 and 55.8 min/d, respectively; P<0.01) in the increase phase. Energy intake decreased (-463.0 kcal/d; P<0.01) when sedentary behaviors decreased: the decrease in fat intake was -295.2 kcal/d (P<0.01). No significant changes in energy intake were observed when sedentary behaviors were increased. Youth also increased their activity by 102.4 activity counts min-1d-1 (estimated at 113.1 kcal) when sedentary behaviors were decreased (P<0.05). Decreasing sedentary behaviors can decrease energy intake in nonoverweight adolescent youth and should be considered an important component of interventions to prevent obesity and to regulate body weight.


Childhood socioeconomic position and adult leisure-time physical activity: a systematic review.
Regular leisure-time physical activity (LTPA) benefits health and is thought to be less prevalent in lower socioeconomic groups. Evidence suggests that childhood socioeconomic circumstances can impact on adult health and behaviour however, it is unclear if this includes an influence on adult LTPA. This review tested the hypothesis that a lower childhood socioeconomic position (SEP) is associated with less frequent LTPA during adulthood. Studies were located through a systematic search of MEDLINE, Embase, PsycINFO, CINAHL and SPORTDiscus and by searching reference lists. Eligible studies were English-language publications testing the association between any indicator of childhood SEP and an LTPA outcome measured during adulthood. Forty-five papers from 36 studies, most of which were European, were included. In most samples, childhood SEP and LTPA were self-reported in midlife. Twenty-two studies found evidence to support the review's hypothesis and thirteen studies found no association. Accounting for own adult SEP partly attenuated associations. There was more evidence of an association in British compared with Scandinavian cohorts and in women compared with men. Results did not vary by childhood SEP indicator or age at assessment of LTPA. This review found evidence of an association between less advantaged childhood SEP and less frequent LTPA during adulthood. Understanding how associations vary by gender and place could provide insights into underlying pathways.


Metabolic stress regulates ERK activity by controlling KSR-RAF heterodimerization.
Altered cell metabolism is a hallmark of cancer, and targeting specific metabolic nodes is considered an attractive strategy for cancer therapy. In this study, we evaluate the effects of metabolic stressors on the deregulated ERK pathway in melanoma cells bearing activating mutations of the NRAS or BRAF oncogenes. We report that metabolic stressors promote the dimerization of KSR proteins with CRAF in NRAS-mutant cells, and with oncogenic BRAF in BRAFV600E-mutant cells, thereby enhancing ERK pathway activation. Despite this similarity, the two genomic subtypes react differently when a higher level of metabolic stress is induced. In NRAS-mutant cells, the ERK pathway is even more stimulated, while it is strongly downregulated in BRAFV600E-mutant cells. We demonstrate that this is caused by the dissociation of mutant BRAF from KSR and is mediated by activated AMPK. Both types of ERK regulation nevertheless lead to cell cycle arrest. Besides studying the effects of the metabolic stressors on ERK pathway activity, we also present data suggesting that for efficient therapies of both genomic melanoma subtypes, specific metabolic targeting is necessary.


Healthcare teams as complex adaptive systems: Focus on interpersonal interaction.
The aim of this study is to test the feasibility of a tool to objectify the functioning of healthcare teams operating in the complexity zone, and to evaluate its usefulness in identifying areas for team quality improvement. We distributed The Complex Adaptive Leadership (CAL™) Organisational Capability Questionnaire (OCQ) to all members of one palliative care team (n=15) and to palliative care physicians in Flanders, Belgium (n=15). Group discussions were held on feasibility aspects and on the low scoring topics. Data was analysed calculating descriptive statistics (sum score, mean and standard deviation). The one sample T-Test was used to detect differences within each group. Both groups of participants reached mean scores ranging from good to excellent. The one sample T test showed statistically significant differences between participants' sum scores within each group (p<0,001). Group discussion led to suggestions for quality improvement e.g. enhanced feedback strategies between team members. The questionnaire used in our study shows to be a feasible and useful instrument for the evaluation of the palliative care teams' day-to-day operations and to identify areas for quality improvement. The CAL™OCQ is a promising instrument to evaluate any healthcare team functioning. A group discussion on the questionnaire scores can serve as a starting point to identify targets for quality improvement initiatives.


Human-caused Indo-Pacific warm pool expansion.
The Indo-Pacific warm pool (IPWP) has warmed and grown substantially during the past century. The IPWP is Earth's largest region of warm sea surface temperatures (SSTs), has the highest rainfall, and is fundamental to global atmospheric circulation and hydrological cycle. The region has also experienced the world's highest rates of sea-level rise in recent decades, indicating large increases in ocean heat content and leading to substantial impacts on small island states in the region. Previous studies have considered mechanisms for the basin-scale ocean warming, but not the causes of the observed IPWP expansion, where expansion in the Indian Ocean has far exceeded that in the Pacific Ocean. We identify human and natural contributions to the observed IPWP changes since the 1950s by comparing observations with climate model simulations using an optimal fingerprinting technique. Greenhouse gas forcing is found to be the dominant cause of the observed increases in IPWP intensity and size, whereas natural fluctuations associated with the Pacific Decadal Oscillation have played a smaller yet significant role. Further, we show that the shape and impact of human-induced IPWP growth could be asymmetric between the Indian and Pacific basins, the causes of which remain uncertain. Human-induced changes in the IPWP have important implications for understanding and projecting related changes in monsoonal rainfall, and frequency or intensity of tropical storms, which have profound socioeconomic consequences.


The eye examination in the evaluation of child abuse.
Retinal hemorrhage is an important indicator of possible abusive head trauma, but it is also found in a number of other conditions. Distinguishing the type, number, and pattern of retinal hemorrhages may be helpful in establishing a differential diagnosis. Identification of ocular abnormalities requires a full retinal examination by an ophthalmologist using indirect ophthalmoscopy through a pupil that has been pharmacologically dilated. At autopsy, removal of the eyes and orbital tissues may also reveal abnormalities not discovered before death. In previously well young children who experience unexpected apparent life-threatening events with no obvious cause, children with head trauma that results in significant intracranial hemorrhage and brain injury, victims of abusive head trauma, and children with unexplained death, premortem clinical eye examination and postmortem examination of the eyes and orbits may be helpful in detecting abnormalities that can help establish the underlying etiology.


Effects of alterations in the immunocompetent status of Mus musculus females on the survival of transferred Mus caroli embryos.
The role of the immune system in promoting the midterm death of Mus caroli embryos transferred to the Mus musculus uterus was studied in vivo by transferring M. caroli blastocysts to recipients with altered immune status. Transfers of embryos to chimaeric mothers (Mus musculus in equilibrium Mus caroli), which were expected to be tolerant of species antigens, resulted in survival of M. musculus embryos but death of M. caroli embryos. The preferential survival of M. musculus embryos was explained by showing that M. musculus embryos can survive in the M. caroli uterus. Transfers to T cell-deficient mice of genotype nu/nu and to NK cell-deficient mice of genotype bg/bg as well as treatment of normal transfer recipients with Cyclosporin A or anti-Ia antiserum failed to prolong survival. However, immunization of recipients with M. caroli lymphocytes promoted more rapid and uniform failure of the interspecies pregnancy. Cytotoxic cells were detected in the resorbing embryos on Day 10.5 in immune pregnancies and on Day 12.5 in non-immune pregnancies and these cells were promiscuous in their pattern of lysis, showing equal reactivity against M. caroli, transfer recipient and 3rd party target cells. These experiments show that failure of M. caroli embryos in the M. musculus uterus is complex, but probably does not involve responses by classical cytotoxic T lymphocyte or natural killer cell pathways. Participation of the immune system in the resorption process, however, is confirmed and is associated with generation of promiscuous cytolytic cells.


[Nutrition and health--obesity].
About 12% of the adult Dutch population is obese (Quetelet Index > or = 30 kg/m2). The prevalence has roughly doubled over the past 20 years. Obesity is strongly associated with a number of chronic diseases, such as type 2 diabetes mellitus, increased healthcare costs and a loss of productivity. Obesity is always the result of a mismatch between energy intake and energy expenditure. Foods with a high percentage of energy derived from fat are associated with weight gain, particularly when the rest of the energy is obtained from products containing little dietary fibre. Foods with a high content of refined added sugars or starch might be unfavourable with respect to the energy balance and the risk for type 2 diabetes mellitus and cardiovascular diseases. Slimming diets should aim for a gradual and sustained weight loss of about 10% of the initial weight over a period of six months, followed by weight maintenance over the next two years. Physical activity is an essential component of a weight loss strategy. Moderate sustained weight loss is associated with a strong reduction in the risk of type 2 diabetes mellitus in people with impaired glucose tolerance.


Effects of interprofessional rural training on students' perceptions of interprofessional health care services.
Interprofessional training has been advocated in the education of students in health care professions to facilitate collaboration and cooperation among health care providers. This study reported on one facet of the outcomes of a larger grant project funded by the Department of Health and Human Services HRSA grant #1-D36 AH 10082-03, which aimed to develop a new and innovative model for interprofessional student training. Over the 3-year period of the project, a total of 111 students from allied health professions including occupational therapy, physical therapy, and pharmacy participated in the project training. Participants' perceptions on interprofessional service were assessed before and after they participated in the project by the Interprofessional Education Perception Scale. Results of a univariate repeated measures two-way analysis of variance revealed a significant increase in participants' positive perceptions regarding interprofessional practice after they participated in the project (p < 0.05), and the significant increases were independent of the duration of the training (p < 0.01 for short-term and long-term training). A significant interaction between the duration of the training and pretest and posttest scores of the participants was found (p < 0.05) and students who participated in long-term training reported more positive attitudes on the posttest. These encouraging findings are supported and strengthened further by the qualitative data of the study, suggesting the training project has a significant impact on allied health students' perceptual attitudes toward interprofessional service delivery. Findings of the study are discussed related to the improvement of quality care and to the recruitment and retentions of health care providers in rural and underserved areas.


Woodchuck hepatitis virus posttranscriptional regulatory element enhances expression of transgenes delivered by retroviral vectors.
The expression of genes delivered by retroviral vectors is often inefficient, a potential obstacle for their widespread use in human gene therapy. Here, we explored the possibility that the posttranscriptional regulatory element of woodchuck hepatitis virus (WPRE) might help resolve this problem. Insertion of the WPRE in the 3' untranslated region of coding sequences carried by either oncoretroviral or lentiviral vectors substantially increased their levels of expression in a transgene-, promoter- and vector-independent manner. The WPRE thus increased either luciferase or green fluorescent protein production five- to eightfold, and effects of a comparable magnitude were observed with either the immediate-early cytomegalovirus or the herpesvirus thymidine kinase promoter and with both human immunodeficiency virus- and murine leukemia virus-based vectors. The WPRE exerted this influence only when placed in the sense orientation, consistent with its predicted posttranscriptional mechanism of action. These results demonstrate that the WPRE significantly improves the performance of retroviral vectors and emphasize that posttranscriptional regulation of gene expression should be taken into account in the design of gene delivery systems.


A randomised trial of oral versus intravenous opioids for treatment of pain after cardiac surgery.
Cardiac surgery and sternotomy are procedures accompanied by substantial postoperative pain which is challenging to treat. In general, intravenous (IV) opioids are used in the immediate postoperative phase, followed by oral opioids. Oral opioids are easier to use and generally less expensive. Our goal was thus to determine whether a new opioid preparation provides adequate analgesia after sternotomy. In particular, we tested the primary hypothesis that total opioid use (in morphine equivalents) is not greater with oral opioid compared with patient-controlled IV morphine. Our secondary hypothesis was that analgesic efficacy is similar with oral and IV opioids. A total of 51 patients having elective cardiac surgery were enrolled in this study. After rapid postoperative respiratory weaning, the patients were randomised into one of two groups receiving different types of analgesia: oral Targin (a combination of oxycodone-hydrochloride and the opioid antagonist naloxone hydrochloride-dihydrate) or patient-controlled IV morphine. Pain score (visual analogue scale), sedation (Ramsey score), respiratory rate and side effects were assessed at 3, 5, 7, 9 and 11 h after surgery, and every 6 h throughout the third postoperative evening. The total opioid dose in morphine equivalent doses was significantly lower with oral opioid than with IV morphine (adjusted geometric means [95 % confidence interval]: 34 [29; 38] vs. 69 [61; 78] mg, respectively). Pain scores were similar in each group. Analgesic quality was comparable with oral and IV opioids, suggesting that postoperative pain even after very painful procedures can be sufficiently managed with oral opioids.


Influence of grain size and veneer firing process on the flexural strength of zirconia ceramics.
The aim of the present investigation was to study the influence of grain size on the strength of yttria-stabilized zirconia upon exposure to an additional heat treatment, mimicking the veneering process. The green bodies of zirconia discs prepared by cold isostatic pressing were sintered at 1,425, 1,500, or 1,575°C to customize the grain size. The disc-shaped specimens were highly polished and then processed with or without additional heat treatments (five times at 850-930°C). Ten specimens from each treatment group were subjected to a biaxial flexural strength test according to the ISO 6872 standard. The grain size of the specimens was analyzed by the mean linear intercept technique using scanning electron microscopy. It was demonstrated that the mechanical strength of zirconia ceramics was not reduced by the veneer firing processes when polished specimens were used, but the strength was found to decrease with increasing grain size. The raw materials and the sintering process used should be selected appropriately to avoid grain coarsening because it was found that the strength was influenced by large grains.


Combining naltrexone and prazosin in a single oral medication decreases alcohol drinking more effectively than does either drug alone.
Naltrexone (NTX) is underutilized in clinical treatment settings because its efficacy is modest, and it is not effective for all alcoholics and, when it is effective, a significant number of alcoholics fail to maintain initial treatment gains and subsequently relapse to heavy drinking. This has slowed acceptance of NTX by the treatment community, and there is a clear need for additional treatments for alcoholism and alcohol use disorders. Given that NTX and prazosin can each reduce alcohol drinking in rats selectively bred for alcohol preference and high voluntary alcohol drinking (alcohol-preferring "P" rats), we tested whether a combination of NTX + prazosin is more effective in decreasing alcohol drinking than is either drug alone. P rats were given access to a 15% (v/v) alcohol solution for 2 hours daily. Rats were fed NTX and prazosin, alone or in combination, prior to onset of the daily 2-hour alcohol access period for 4 weeks and the effect of drug treatment on alcohol and water intake was assessed. During the first week of treatment, neither a low dose of NTX, nor prazosin, was effective in decreasing alcohol intake when each drug was administered alone, but combining the 2 drugs in a single medication significantly reduced alcohol intake. The combination was as effective as was a higher dose of NTX. Using a low dose of NTX in combination with prazosin may reduce the potential for undesirable side effects early in treatment which, in turn, may improve patient compliance and result in a more successful outcome when NTX is used for treating alcoholism and alcohol use disorders. Combining low-dose NTX and prazosin in a single medication may be more useful than is either drug alone for treating both inpatient and outpatient alcoholics and heavy drinkers early in the treatment process.


Coping and quality of life in Turkish women living with ovarian cancer.
This study investigated the utilization of both problem and emotion focused coping strategies and their association with aspects of quality of life among Turkish women with ovarian cancer undergoing chemotherapy. The convenience sample consisted of 228 patients in all disease stages. The data were collected using the brief COPE, QOL-Cancer patient tool, sociodemographic sheet, and medical variables were gathered from patients' medical charts. Findings reveal that quality of life is moderately high for this group of cancer patients, despite some specific negative facets of the illness and treatment experience. Acceptance, emotional support and religion were the most frequently used problem-focused coping strategies and self-distraction, venting and behavioral disengagement were the most frequently used emotion-focused coping strategies reported by patients. Overall quality of life and, particularly, psychological and spiritual well- being scores of younger patients were lower. Patients reported using significantly more problem-focused coping than emotion-focused coping, and more problem-focused and less emotion-focused coping predicted greater quality of life. Problem-focused coping was related to patients' physical and spiritual well-being and emotion- focused coping was related inversely with psychological and social well-being. Coping strategies are influential in patient quality of life and their psychosocial adaptation to ovarian cancer. Psycho-oncology support programs are needed to help patients to frequent use of problem-focused coping and reduce emotion- focused coping strategies to improve overall quality of life.


Delinquency Among Adolescents with Disabilities.
This study expands upon previous research by utilizing nationally representative data and multivariate analyses to examine the relationship between an adolescent's disability status and their likelihood of engaging in a spectrum of delinquent behaviors through age 16. Logistic regression models of 7,232 adolescents from the National Longitudinal Survey of Youth 1997 are used to investigate the association between the presence of a learning disability or emotional condition, chronic health condition, sensory condition, physical disability, or multiple conditions and ten delinquent acts, including violence-related delinquency, property crimes, drug offenses, and arrest. Additional analyses explore differences in delinquency prevalence by more specific types of limiting conditions. Results indicate that adolescents with learning disabilities or emotional conditions are particularly at risk of committing delinquent acts. Findings suggest that disability status is important to consider when examining adolescent delinquency; however, not all youth with disabilities have equal experiences.


Chronic toxicity of an environmentally relevant and equitoxic ratio of five metals to two Antarctic marine microalgae shows complex mixture interactivity.
Metal contaminants are rarely present in the environment individually, yet environmental quality guidelines are derived from single-metal toxicity data. Few metal mixture studies have investigated more than binary mixtures and many are at unrealistically high effect concentrations to freshwater organisms. This study investigates the toxicity of five metals (Cd, Cu, Ni, Pb, and Zn) to the Antarctic marine microalgae Phaeocystis antarctica and Cryothecomonas armigera. Two mixtures were tested: (i) an equitoxic mixture of contaminants present at their single-metal EC10 concentrations, and (ii) an environmental mixture based on the ratio metal concentrations in a contaminated Antarctic marine bay. Observed toxicity, as chronic population growth rate inhibition, was compared to Independent Action (IA) and Concentration Addition (CA) predictions parameterised to use EC10 values. This allowed for the inclusion of metals with low toxicities. The biomarkers chlorophyll a fluorescence, cell size and complexity, and intracellular lipid concentrations were assessed to investigate possible mechanisms behind metal-mixture interactions. Both microalgae had similar responses to the equitoxic mixture: non-interactive by IA and antagonistic by CA. Toxicity from the environmental mixture was antagonistic by IA to P. antarctica; however, to C. armigera it was concentration-dependent with antagonism at low toxicities and synergism at high toxicities by both IA and CA. Differences in dissolved organic carbon production and detoxification mechanisms may be responsible for these responses and warrants further investigation. This study shows that mixture toxicity interactions can be ratio, species, and concentration dependent. The responses of the microalgae to different mixture ratios highlight the need to assess toxicity at environmentally realistic metal ratios. Parameterising IA and CA reference models to use EC10s allowed for the inclusion of metals at low effect concentrations, which may otherwise be ignored. Reference mixture models are generally suitable for predicting chronic toxicity of metals to these marine microalgae at environmentally realistic ratios and concentrations.


Multivariate phenotype association analysis by marker-set kernel machine regression.
Genetic studies of complex diseases often collect multiple phenotypes relevant to the disorders. As these phenotypes can be correlated and share common genetic mechanisms, jointly analyzing these traits may bring more power to detect genes influencing individual or multiple phenotypes. Given the advancement brought by the multivariate phenotype approaches and the multimarker kernel machine regression, we construct a multivariate regression based on kernel machine to facilitate the joint evaluation of multimarker effects on multiple phenotypes. The kernel machine serves as a powerful dimension-reduction tool to capture complex effects among markers. The multivariate framework incorporates the potentially correlated multidimensional phenotypic information and accommodates common or different environmental covariates for each trait. We derive the multivariate kernel machine test based on a score-like statistic, and conduct simulations to evaluate the validity and efficacy of the method. We also study the performance of the commonly adapted strategies for kernel machine analysis on multiple phenotypes, including the multiple univariate kernel machine tests with original phenotypes or with their principal components. Our results suggest that none of these approaches has the uniformly best power, and the optimal test depends on the magnitude of the phenotype correlation and the effect patterns. However, the multivariate test retains to be a reasonable approach when the multiple phenotypes have none or mild correlations, and gives the best power once the correlation becomes stronger or when there exist genes that affect more than one phenotype. We illustrate the utility of the multivariate kernel machine method through the Clinical Antipsychotic Trails of Intervention Effectiveness antibody study.


Exercise therapy in women who have had breast cancer: design of the Sheffield women's exercise and well-being project.
Recovering from cancer treatment can be a difficult experience, both physically and psychologically. This paper describes a randomized controlled trial that evaluates the effects of exercise therapy upon quality of life in 120 women who have had breast cancer. To facilitate behaviour change, exercise counselling is also included as an integral component in the exercise therapy intervention. Participants are randomized to one of three groups: exercise therapy, body conditioning (placebo control) or a normal care control group. The supervised exercise therapy and body conditioning sessions take place 3 times per week for 8 weeks. Outcome measures include quality of life, physical self-perceptions, depression, satisfaction with life, exercise behaviour, aerobic capacity and percentage body fat. All outcomes are assessed at baseline, 4 weeks during the intervention and at the end of the 8-week intervention. Follow-up assessments of outcomes take place at 3 and 6 months post-intervention. As the number of women surviving breast cancer is increasing and cancer treatment is linked to reduced quality of life, it is critical to evaluate treatments that improve the quality of life of this population or hasten recovery following treatment.


The Bone Regeneration Using Bone Marrow Stromal Cells with Moderate Concentration Platelet-Rich Plasma in Femoral Segmental Defect of Rats.
Platelet-rich plasma (PRP) can provide an assortment of growth factors, but how PRP effects bone regeneration is still unknown. The aim of the study was to explore an optimal method of using PRP and bone marrow stromal cells (BMSCs). An in vitro experiment was first conducted to determine an appropriate quantity of PRP. BMSCs were cultured with PRP of different concentrations to assess cell proliferation and osteogenic differentiation. Following the in vitro study, a rat femoral segmental defect model was used. Five collagen mixtures consisting of different concentrations of PRP and BMSCs were prepared as follows, i) BMSCs and PRP (platelet 20 x 104/µl), ii) BMSCs and PRP (platelet 100 x 104/µl), iii) BMSCs and PRP (platelet 500 x 104/µl), iv) BMSCs, and v) PRP group (platelet 100 x 104/µl), were used to fill defect. New bone formation was evaluated by soft X-ray and histologic analyses were performed at 2, 4, 6 and 8 weeks postoperatively. The cell proliferation increased PRP concentration-dependently. Cellular alkaline phosphatase activity was higher in moderate concentration than high or low concentration group's in vitro study. In vivo study, the bone fill percentage of newly formed bone in BMSCs and PRP (platelet 100 x 104/µl) was 46.9% at 8 weeks and increased significantly compared with other groups. BMSCs with moderate level of PRP significantly enhanced bone formation in comparison with BMSCs or PRP transplant in a rat femoral defect model.


Cytogenetic and histologic correlations in malignant lymphoma.
Although a number of studies have indicated correlations between histologic subtypes of tumors and certain nonrandom chromosome changes, cytogenetic studies of lymphoma are in an early stage compared to those of leukemia. No comprehensive analysis of available data has so far been attempted in the literature either. Here we present an analysis of chromosome changes and their correlation with subtypes of lymphoma studied by conventional histology and cell surface markers, as observed in two sets of data: a group of 65 karyotypically abnormal tumors sequentially ascertained and studied by us during the period January 1, 1984 to April 30, 1985, and a larger data set derived by combining our data with those from two published series from the University of Minnesota that are comparable to our data. These combined data, which comprise the largest data set on the cytogenetics of lymphomas assembled so far, enabled a comprehensive analysis of correlation between chromosome change and tumor histology and the patterns of chromosome instability in these tumors. We found several significant associations, some previously described and others now recognized, between nonrandom chromosome gains, breaks, translocations, and deletions and histologic subtypes of tumors that characterize lymphomas. The data indicate that finding of chromosome breaks at certain sites (eg, 8q24, 14q32, 18q21) is of diagnostic value in dealing with cases of unusual lymphoma. Furthermore, nonrandom chromosome breakage exhibited three distinct patterns that reflected three levels of etiologically relevant genetic change.


A new method to measure local oxygen consumption in human skeletal muscle during dynamic exercise using near-infrared spectroscopy.
Near infrared spectroscopy (NIRS) can readily report on changes in blood volume and oxygenation. However, it has proved more problematic to measure real-time changes in blood flow and oxygen consumption. Here we report the development of a novel method using NIRS to measure local oxygen consumption in human muscle. The method utilizes the blood volume changes induced by the muscle pump during rhythmically contracting exercising skeletal muscle. We found that the saturation of the blood during the contraction phase was lower than that during the relaxation phase. The calculated oxygen drop was then divided by the contraction time to generate a value for the muscle oxygen consumption in the optical region of interest. As a test we measured the muscle oxygen consumption in the human vastus lateralis during exercise on a cycle ergometer by 11 trained male athletes (32 +/- 11 years old) at 40% and 110% peak aerobic power. We saw an increase from 13.78 micromol 100 g(-1) min(-1) to 19.72 micromol 100 g(-1) min(-1) with the increase in power. The measurements are theoretically exempt from usual NIRS confounders such as myoglobin and adipose tissue and could provide a useful tool for studying human physiology.


Evaluating the Psychosocial Impact of Indoor Public Spaces in Complex Healthcare Settings.
This article describes an approach to a metrics-based evaluation of public space in hospitals using cross-disciplinary qualitative and quantitative analyses. The method, Indoor Public Space Measurement (IPSM), is well suited to researchers and designers who intend to evaluate user-centered spatial solutions in hospitals and similar facilities. Healthcare is transiting toward a value-based policy at all levels. Choosing the right set of qualitative and quantitative analyses to support value-based design solutions is not always an easy journey for healthcare design consultants. This article seeks to pull together the key analyses to evaluate the impact of the hospital indoor public space on the psychosocial well-being of the hospital users. A step-by step guide to performing key analyses to evaluate the impact of hospital indoor public space environment on the users' psychosocial well-being is provided. A case study from the authors' research is utilized to illustrate the application of the method. Interpolating the results of all the analyses, the reader can identify where in the layout most of interactions among users occur, identify their typology and evaluate the contribution to the general psychosocial well-being, and know which group of users is more exposed to a specific typology of interaction. The IPSM method can help design consultants to measure the impact of the built environment of hospital public space on its occupants' psychosocial well-being: factual knowledge about the users' behavioral response with respect to wayfinding and social interaction. The application of the method is not limited to healthcare settings only.


Design of a filamentous polymeric scaffold for in vivo guided angiogenesis.
Angiogenesis is mandatory for reperfusion of viable tissues, and lack of vascularization may cause ischemia. The increasing disparity between the demand and availability of adequate substitutes for small-diameter human blood vessels has prompted an intensive search for artificial materials or biological allograft tissues, both of which usually fail in the long term. The objective of this study was to pioneer a novel model for in vivo guided angiogenesis based on a specific design process of a filamentous polymeric scaffold with endothelial cells in a 3-dimensional culture system. To our knowledge, this is the first report of an in vivo guided angiogenesis approach based on a 2-step model, composed of endothelial cells and a filamentous polymeric scaffold framework. Endothelial cells that had been cultured on a specifically designed filamentous polymeric scaffold within a regulated dynamic tissue culture system were shown in vivo to induce guided angiogenesis. Cells seeded on a biodegradable polymeric scaffold were implanted into mice. On day 28 after implantation, analysis revealed a guided angiogenic process along the path of the implanted polymeric scaffold as well as initial evidence for early maturation of engineered vessels, allowing red blood cells to flow through the forming lumina of new vessels as the polymer degraded. The authors conclude that in vivo guided angiogenesis can be achieved by combining endothelial cells with biodegradable filamentous polymeric scaffolds and that this model can lay the cornerstone for vascular engineering and future development of clinically available protocols aimed to treat life-threatening cardiovascular conditions.


Primary amoebic meningoencephalitis with subsequent organ procurement: a case study.
Primary amoebic meningoencephalitis (PAM) is a rare and rapidly fatal disease caused by the Naegleria fowleri amoeba. It is a diagnosis rarely seen by medical personnel, yet this amoeba is frequently encountered by people who frequent freshwater bodies of water in certain states. The disease primarily affects children and young adults who swim or take part in water sports in the waters in which the amoeba thrive. The disease presents with symptomatology similar to bacterial meningitis: headache, stiff neck, altered mental status, seizures, and coma with a quick progression to death. Rapid diagnosis is imperative to facilitate prompt treatment, although PAM has 95% mortality. There have been only 10 survivors reported in medical literature. This disease is a public-health risk to those living in affected areas of the country. Healthcare providers need to be cognizant of the disease as well, and, although recovery is rare, focus on prevention and risk reduction strategies is imperative. It is not completely understood why, of the millions of people are exposed to freshwater with the amoeba, only a few become infected with it. The Centers for Disease Control and Prevention have suggested that all freshwater areas should always assume a level of risk in waters, even when signage is not posted. This case study will review a fatal case of Naegleria fowleri infection in a young patient and will include the pathophysiology, diagnosis, treatment, nursing and public health implications, and organ procurement that occurred with the patient.


Discovering New Genes in the Pathways of Common Sporadic Neurodegenerative Diseases: A Bioinformatics Approach.
Late onset Alzheimer's disease (AD) and Parkinson's disease (PD) are mostly "sporadic" age-related neurodegenerative disorders, but with a clear genetic component. However, their genetic architecture is complex and heterogeneous, largely remaining a conundrum, with only a handful of well-established genetic risk factors consistently associated with these diseases. It is possible that numerous, yet undiscovered, AD and PD related genes might exist. We focused on the 'gene' as a mediator to find new potential genes that might have a relationship with both disorders using bio-literature mining techniques. Based on Entrez Gene, we extracted the genes and directional gene-gene relation in the entire MEDLINE records and then constructed a directional gene-gene network. We identified common genes associated with two different but related diseases by performing shortest path analysis on the network. With our approach, we were able to identify and map already known genes that have a direct relationship with PD and AD. In addition, we identified 7 genes previously unknown to be a bridge between these two disorders. We confirmed 4 genes, ROS1, FMN1, ATP8A2, and SNORD12C, by biomedical literature and further checked 3 genes, ERVK-10, PRS, and C7orf49, that might have a high possibility to be related with both diseases. Additional experiments were performed to demonstrate the effectiveness of our proposed method. Comparing to the co-occurrence approach, our approach detected 25% more candidate genes and verified 10% more genes that have the relationship between both diseases than the co-occurrence approach did.


Febrile neutropenia: outline of management.
Febrile neutropenia is a common emergency encountered in children receiving chemotherapy for a malignancy. Left untreated, it can lead to serious morbidity and mortality. Febrile neutropenia is suspected in any patient on chemotherapy who presents with fever. Prompt evaluation and management by the primary contact pediatrician is essential for a successful outcome. A detailed history and physical examination is warranted to identify source of infection, although two thirds of them may not have localizing symptoms or signs. Risk stratification is valuable in categorizing the severity and guiding therapy. Initial stabilization, prompt initiation of appropriate antibiotics and adequate supportive care are the cornerstone of treatment. Knowledge of the locally prevailing bacteriological profile and antimicrobial susceptibility data is crucial for each hospital/unit to frame and periodically modify guidelines for the choice of antimicrobials. Delay in initiating antimicrobials significantly worsens the outcome. Education of the family as well as the members of the treating unit is important in this regard. Pro-active steps must be taken to reduce incidence of hospital acquired sepsis. Diagnosis and management in relevance to the emergency room is reviewed and institutional practice is shared.


Obstructive Sleep Apnea in Adults: The Role of Upper Airway and Facial Skeletal Surgery.
Obstructive sleep apnea represents a large burden of disease to the general population and may compromise patient quality of life; workplace and automotive safety; and metabolic, cardiovascular, and neurocognitive health. The disease is characterized by repetitive cycles of upper airway collapse resulting from a lack of pharyngeal airway structural support and loss of muscle tone among upper airway dilators. Polysomnography serves as the gold standard for diagnosis of obstructive sleep apnea and the apnea-hypopnea index is the most commonly used metric for quantifying disease severity. Conservative treatments include lifestyle modification, continuous positive airway pressure treatment, and dental appliance therapy. Surgical treatment options include pharyngeal and facial skeletal surgery. Maxillomandibular advancement has been shown to be the most effective surgical approach for multilevel expansion of the upper airway and may significantly reduce an obstructive sleep apnea patient's apnea-hypopnea index. Patient age, obesity, and the degree of maxillary advancement may be key factors contributing to treatment success.


Implementation of a urogynecology-specific enhanced recovery after surgery (ERAS) pathway.
Enhanced recovery after surgery protocols were developed for colorectal surgery to hasten postoperative recovery. Variations of the protocol are being adopted for gynecological procedures despite limited population and procedure-specific outcome data. Our objective was to evaluate whether implementation of an enhanced recovery after surgery pathway would facilitate reduced length of admission in a urogynecology population. In this retrospective analysis of patients undergoing pelvic floor reconstructive surgery by 7 female pelvic medicine and reconstructive surgeons, we compared same-day discharge, length of admission and postoperative complications before and after implementation of an enhanced recovery after surgery pathway at a tertiary care hospital. Groups were compared using χ2 and Student t tests. Candidate variables that could have an impact on patient outcomes with P < .2 were included in multivariable logistic regression models. Satisfaction with surgical experience was assessed using a phone-administered questionnaire the day after discharge. Mean age and body mass index of 258 women (137 before enhanced recovery after surgery and 121 enhanced recovery after surgery) were 65.5 ± 11.3 years and 28.2 ± 5.0 kg/m2. The most common diagnosis was pelvic organ prolapse (n = 242, 93.8%) including stage III pelvic organ prolapse (n = 61, 65.1%). Apical suspension procedures included 58 transvaginal (25.1%), 112 laparoscopic/robotic (48.8%), and 61 obliterative (26.4%). Hysterectomy was performed in 57.4% of women. Demographic and surgical procedures were similar in both groups. Compared with before enhanced recovery after surgery, the enhanced recovery after surgery group had a higher proportion of same-day discharge (25.9% vs 91.7%, P < .001) and a 13.8 hour shorter duration of stay (25.9 ± 13.5 vs 12.1 ± 11.2 hours, P <.001). Operative and postsurgical recovery room times were similar (2.6 ± 0.8 vs 2.6 ± 0.9 hours, P =.955; 3.7 ± 2.1 vs 3.6 ± 2.2 hours, P = .879). Women in the enhanced recovery after surgery group were more likely to be discharged using a urethral catheter (57.9% enhanced recovery after surgery vs 25.4% before enhanced recovery after surgery, P = .005). There were no group differences in total 30 day postoperative complications overall and for the following categories: urinary tract infections, emergency room visits, unanticipated office visits, and return to the operating room. However, enhanced recovery after surgery patients had higher 30 day hospital readmission rates (n = 8, 6.7% vs n = 2, 1.5%, P = .048). Patients before enhanced recovery after surgery were readmitted for myocardial infarction and chest pain. Enhanced recovery after surgery patients were admitted for weakness, chest pain, hyponatremia, wound complications, nausea/ileus, and ureteral obstruction. Three enhanced recovery after surgery patients returned to the operating room for ureteral obstruction (n = 1), incisional hernia (n = 1), and vaginal cuff bleeding (n = 1). Enhanced recovery after surgery patients also had more postoperative nursing phone notes (2.6 ± 1.7 vs 2.1 ± 1.4, P = .030). On multivariable logistic regressions adjusting for age and operative time, same-day discharge was more likely in the enhanced recovery after surgery group (odds ratio, 32.73, 95% confidence interval [15.23-70.12]), while the odds of postoperative complications and emergency room visits were no different. After adjusting for age, operative time, and type of prolapse surgery, readmission was more likely in the enhanced recovery after surgery group (odds ratio, 32.5, 95% confidence interval [1.1-28.1]). In the enhanced recovery after surgery group, patient satisfaction (n = 77 of 121) was reported as very good or excellent by 86.7% for pain control, 89.6% for surgery preparedness, and 93.5% for overall surgical experience; 89.6% did not recall any postoperative nausea during recovery. Enhanced recovery after surgery implementation in a urogynecology population resulted in a greater proportion of same-day discharge and high patient satisfaction but with slightly increased hospital readmissions within 30 days.


The National Eye Institute Visual Function Questionnaire in the Macular Telangiectasia (MacTel) Project.
To describe vision-targeted health-related quality of life (HR-QOL), measured with the National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) in a cohort of patients with macular telangiectasia (MacTel) type 2 and to evaluate the relationship between visual acuity and NEI-VFQ-25 scores. This was an analysis of cross-sectional baseline data from a longitudinal natural history study. Patients with MacTel type 2 were enrolled in the Natural History Study of The Macular Telangiectasia Project (The MacTel Project). NEI-VFQ-25 were completed at enrollment. Linear correlation and regression analyses were used to relate baseline NEI-VFQ-25 overall and subscale scores to visual acuity. Participants reported lower vision-related functioning measured by the NEI-VFQ-25 in most of the domains measured by the NEI VFQ compared with that of a normal reference group (P < 0.001 for all domains except color vision). Visual acuity was found to be associated with the NEI-VFQ-25 in many of the domains measuring degree of difficulty with common visual activities. This is the first cross-sectional cohort study to assess vision targeted HR-QOL in patients with MacTel type 2. Patients with MacTel type 2 reported markedly reduced visual functioning compared to reports of a normal reference group. These findings provide support to the use of the NEI-VFQ-25 in patients with MacTel type 2 to measure the effect of disease and potential therapies on vision-targeted HR-QOL.


Infection Kinetics and Tropism of Borrelia burgdorferi sensu lato in Mouse After Natural (via Ticks) or Artificial (Needle) Infection Depends on the Bacterial Strain.
Borrelia burgdorferi sl is a complex of pathogen bacteria transmitted to the host by Ixodes ticks. European Ixodes ricinus ticks transmit different B. burgdorferi species, pathogenic to human. Bacteria are principally present in unfed tick midgut, then migrate to salivary glands during blood meal and infect a new host via saliva. In this study, efficiency of transmission in a mouse model of three pathogen species belonging to the B. burgdorferi sl complex, B. burgdorferi sensu stricto (B31, N40, and BRE-13), B. afzelii (IBS-5), and B. bavariensis (PBi) is examined in order to evaluate infection risk after tick bite. We compared the dissemination of the Borrelia species in mice after tick bite and needle injection. Location in the ticks and transmission to mice were also determined for the three species by following infection kinetics. After inoculation, we found a significant prevalence in the brain for PBi and BRE-13, in the heart, for PBi, in the skin where B31 was more prevalent than PBi and in the ankle where both B31 and N40 were more present than PBi. After tick bite, statistical analyses showed that BRE-13 was more prevalent than N40 in the brain, in the bladder and in the inguinal lymph node. When Borrelia dissemination was compared after inoculation and tick bite, we observed heart infection only after tick inoculation of BRE-13, and PBi was only detected after tick bite in the skin. For N40, a higher number of positive organs was found after inoculation compared to tick bite. All European B. burgdorferi sl strains studied were detected in female salivary glands before blood meal and infected mice within 24 h of tick bite. Moreover, Borrelia-infected nymphs were able to infect mice as early as 12 h of tick attachment. Our study shows the need to remove ticks as early as possible after attachment. Moreover, Borrelia tropism varied according to the strain as well as between ticks bite and needle inoculation, confirming the association between some strains and clinical manifestation of Lyme borreliosis, as well as the role played by tick saliva in the efficiency of Borrelia infection and dissemination in vertebrates.


Digital Social Norm Enforcement: Online Firestorms in Social Media.
Actors of public interest today have to fear the adverse impact that stems from social media platforms. Any controversial behavior may promptly trigger temporal, but potentially devastating storms of emotional and aggressive outrage, so called online firestorms. Popular targets of online firestorms are companies, politicians, celebrities, media, academics and many more. This article introduces social norm theory to understand online aggression in a social-political online setting, challenging the popular assumption that online anonymity is one of the principle factors that promotes aggression. We underpin this social norm view by analyzing a major social media platform concerned with public affairs over a period of three years entailing 532,197 comments on 1,612 online petitions. Results show that in the context of online firestorms, non-anonymous individuals are more aggressive compared to anonymous individuals. This effect is reinforced if selective incentives are present and if aggressors are intrinsically motivated.


In vivo acute toxicity of titanium dioxide nanoparticles to mice after intraperitioneal injection.
Because of its excellent optical performance and electrical properties, TiO2 has a wide range of applications in many fields. It is often considered to be physiologically inert to humans. However, some recent studies have reported that nano-sized TiO2 may generate potential harm to the environment and humans. In this paper the in vivo acute toxicity of nano-sized TiO2 particles to adult mice was investigated. Mice were injected with different dosages of nano-sized TiO2 (0, 324, 648, 972, 1296, 1944 or 2592 mg kg(-1)). The effects of particles on serum biochemical levels were evaluated at various time points (24 h, 48 h, 7 days and 14 days). Tissues (spleen, heart, lung, kidney and liver) were collected for titanium content analysis and histopathological examination. Treated mice showed signs of acute toxicity such as passive behavior, loss of appetite, tremor and lethargy. Slightly elevated levels of the enzymes alanine aminotransferase and aspartate aminotransferase were found from the biochemical tests of serum whereas blood urea nitrogen was not significantly affected (P < 0.05). The accumulation of TiO2 was highest in spleen (P < 0.05). TiO2 was also deposited in liver, kidney and lung. Histopathological examinations showed that some TiO2 particles had entered the spleen and caused the lesion of spleen. Thrombosis was found in the pulmonary vascular system, which could be induced by the blocking of blood vessels with TiO2 particles. Moreover, hepatocellular necrosis and apoptosis, hepatic fibrosis, renal glomerulus swelling and interstitial pneumonia associated with alveolar septal thickening were also observed in high-dose groups.


By how much could screening by primary human papillomavirus testing reduce cervical cancer incidence in England?
Objective The replacement of cytology with human papillomavirus testing as the primary cervical screening test in England is imminent. In light of newly available evidence, we revised our previous estimates of the likely impact of primary human papillomavirus testing on incidence of cervical cancer. Method and results Using screening data on women aged 25-64 diagnosed with cervical cancer in England between 1988 and 2012, we previously reported that 38.8% had a negative test six months to six years prior to diagnosis. However, not all of these cancers would be prevented by human papillomavirus testing: for 1.0% the human papillomavirus positive test would come too late (within 18 months of diagnosis) to make a difference; 7.6% will have a negative human papillomavirus test (based on 79.9% sensitivity of human papillomavirus testing in cytology negative women); and 2.0% will develop cancer despite a positive human papillomavirus test. Additionally, we estimate that some women (equivalent to 4.3% of current incidence) whose cancers are currently prevented by cytology-based screening will have a false-negative human papillomavirus test. Conclusion Overall, we estimate that 23.9% (95% CI: 19.3-27.6%) of current cases in women invited for screening could be prevented. Based on 2013 cancer incidence statistics, absolute numbers could be reduced by 487 (95% CI 394 to 563) or 3.4 (95% CI 2.8 to 4.0) per 100,000 women per year.


Aggregation models of potential cyclical trimethylsulfonium dicyanamide ionic liquid clusters.
Raman and infrared spectra of trimethylsulfonium dicyanamide [(CH(3))(3)SN(CN)(2)] are reported and accurately reproduced by DFT methods (B3LYP and B3PW91), MP2, and MP3, and to a lesser extent by the RHF method. The (CH(3))(3)SN(CN)(2) ionic liquid forms two isomeric dimers that are of cyclic structure, one of which is 13 kcal/mol lower in energy than the other. Both isomeric cyclic pairs (versions 1 and 2), [(CH(3))(3)SN(CN)(2)](2), have the potential to further combine and form a common structure containing four pairs of (CH(3))(3)SN(CN)(2). This structure can then conceivably undergo a stacking procedure to form extended ionic liquid nanotubes of eight ionic liquids, [(CH(3))(3)SN(CN)(2)](8). The possible formation of gas phase ionic liquid clusters of two, four, and eight trimethylsulfonium dicyanamide ionic liquids is supported by highly exergonic free energy changes obtained from B3LYP/(6-311+G(d,p)) density functional calculations.


Repression of T-cell function by thionamides is mediated by inhibition of the activator protein-1/nuclear factor of activated T-cells pathway and is associated with a common structure.
Treatment of hyperthyroidism by thionamides is associated with immunomodulatory effects, but the mechanism of thionamide-induced immunosuppression is unclear. Here we show that thionamides directly inhibit interleukin-2 cytokine expression, proliferation, and the activation (CD69 expression) of primary human T lymphocytes. Inhibition of immune function was associated with a repression of DNA binding of the cooperatively acting immunoregulatory transcription factors activator protein 1 (AP-1) and nuclear factor of activated T-cells (NFAT). Likewise, thionamides block the GTPase p21Ras, the mitogen-activated protein kinases, and impair the calcineurin/calmodulin-dependent NFAT dephosphorylation and nuclear translocation. The potency of inhibition correlated with the chemical reactivity of the thionamide-associated sulfur group. Taken together, our data demonstrate that thio-derivates with a common heterocyclic thioureylene-structure mediate a direct suppression of immune functions in T-cells via inhibition of the AP-1/NFAT pathway. Our observations may also explain the clinical and pathological resolution of some secondary, calcineurin, and mitogen-activated protein kinase-associated diseases upon thionamide treatment in hyperthyroid patients. This offers a new therapeutic basis for the development and application of heterocyclic thio-derivates.


Blood lead levels in children aged between 1 and 6 years old in La Plata, Argentina. Identification of risk factors for lead exposure.
Lead has neurotoxic effects in children, even at a very low level in blood. The risk factors (RFs) for lead exposure have not been adequately identified in La Plata. The objectives of this study were to determine mean blood lead levels and identify RFs in children aged 1 to 6 years old living in La Plata and the outskirts. A cross-sectional study was conducted in children who attended primary health care centers for a health check-up. Blood lead levels were determined by atomic absorption spectroscopy, and a socioenvironmental survey was administered to outline RFs. The Mann-Whitney test was used to compare measurements. A multivariate statistical analysis was done to establish the most relevant RFs. A total of 319 children participated (51% were boys); the median (interquartile range) blood lead level was 2.2 pg/dL (1.1-3.6 pg/dL). Significant mean differences in blood lead levels were observed for age≤ 3years old, anemia, pica behavior, overcrowding, dirt floors, and maternal education < 7 years. Age≤ 3years old and pica behavior were both RFs with significant odds ratios (ORs). The OR as adjusted by logistic regression was significant only for age≤ 3years old. The median blood lead level in the studied population was 2.2 pg/dL. The main RFs identified for lead exposure were age≤ 3years old and pica behavior. Other less relevant RFs included anemia, maternal education < 7 years, overcrowding, and dirt floors.


A systematic review of time to diagnosis in children and young adults with cancer.
It is often assumed that prolonged time to diagnosis (TTD) for cancer negatively influences overall survival and survivorship through advanced stage disease at diagnosis. This systematic review assesses existing early diagnosis research in childhood and young adult cancer and aims to identify whether a consensus exists within the literature in relation to the terminology and methodologies used to investigate TTD in this population. Medline, Embase, the Centre for Reviews and Dissemination database and Cochrane library were searched for papers on children and young adults (0-30 years) published from 1948 to the present. Of the 1665 potentially eligible citations identified, 32 papers met the inclusion criteria. The majority of work was in European (n=15) or North American (n=8) populations. Most work focused on brain tumours (n=10), retinoblastomas (n=5) and bone and soft tissue sarcomas (n=4). The majority of studies were in hospital-based settings (n=25), with only seven papers adopting a population-based setting. Summary statistics presented were mostly median TTD, the skewed distribution of the data meant comparisons between studies based on medians were difficult and combining studies within a meta-analysis was not appropriate. Within the childhood and young adult population, TTD for cancer varies between diagnostic groups and with age at diagnosis in the majority of studies. In order that clear conclusions can be drawn from early diagnosis research in children and young adults, specific criteria identifying circumstances in which delay has occurred should accompany a defined time line to diagnosis or treatment in every study.


Controllable Broadband Optical Transparency and Wettability Switching of Temperature-Activated Solid/Liquid-Infused Nanofibrous Membranes.
Inspired by biointerfaces, such as the surfaces of lotus leaves and pitcher plants, researchers have developed innovative strategies for controlling surface wettability and transparency. In particular, great success has been achieved in obtaining low adhesion and high transmittance via the introduction of a liquid layer to form liquid-infused surfaces. Furthermore, smart surfaces that can change their surface properties according to external stimuli have recently attracted substantial interest. As some of the best-performing smart surface materials, slippery liquid-infused porous surfaces (SLIPSs), which are super-repellent, demonstrate the successful achievement of switchable adhesion and tunable transparency that can be controlled by a graded mechanical stimulus. However, despite considerable efforts, producing temperature-responsive, super-repellent surfaces at ambient temperature and pressure remains difficult because of the use of nonreactive lubricant oil as a building block in previously investigated repellent surfaces. Therefore, the present study focused on developing multifunctional materials that dynamically adapt to temperature changes. Here, we demonstrate temperature-activated solidifiable/liquid paraffin-infused porous surfaces (TA-SLIPSs) whose transparency and control of water droplet movement at room temperature can be simultaneously controlled. The solidification of the paraffin changes the surface morphology and the size of the light-transmission inhibitor in the lubricant layer; as a result, the control over the droplet movement and the light transmittance at different temperatures is dependent on the solidifiable/liquid paraffin mixing ratio. Further study of such temperature-responsive, multifunctional systems would be valuable for antifouling applications and the development of surfaces with tunable optical transparency for innovative medical applications, intelligent windows, and other devices.


Metabolic consequences of pregnancy-associated plasma protein-A deficiency in mice: exploring possible relationship to the longevity phenotype.
Mice born with the deletion of the gene for pregnancy-associated plasma protein-A (PAPP-A), a model of reduced local IGF activity, live approximately 30% longer than their wild-type (WT) littermates. In this study, we investigated metabolic consequences of PAPP-A gene deletion and possible relationship to lifespan extension. Specifically, we determined whether 18-month-old PAPP-A knockout (KO) mice when compared with their WT littermates have reduced energy expenditure and/or altered glucose-insulin sensitivity. Food intake, and total energy expenditure and resting energy expenditure as measured by calorimetry were not different between PAPP-A KO and WT mice when subjected to the analysis of covariance with body weight as the covariate. However, there was an increase in spontaneous physical activity in PAPP-A KO mice. Both WT and PAPP-A KO mice exhibited mild insulin resistance with age, as assessed by fasting glucose/insulin ratios. Oral glucose tolerance and insulin sensitivity were not significantly different between the two groups of mice, although there appeared to be a decrease in the average size of the pancreatic islets in PAPP-A KO mice. Thus, neither reduced 'rate of living' nor altered glucose-insulin homeostasis can be considered key determinants of the enhanced longevity of PAPP-A KO mice. These findings are discussed in the context of those from other long-lived mouse models.


Seasonal variation of arsenic and antimony in surface waters of small subarctic lakes impacted by legacy mining pollution near Yellowknife, NT, Canada.
The seasonal variation in lake water arsenic (As) and antimony (Sb) concentrations was assessed in four small (<1.5km2) subarctic lakes impacted by As and Sb emissions from legacy mining activities near Yellowknife, Northwest Territories, Canada. Substantial variation in As concentrations were measured over the two-year period of study in all but the deepest lake (maximum depth 6.9m), including a four-fold difference in As in the shallowest lake ([As]: 172-846μgL-1; maximum depth 0.8m). Arsenic concentrations were enriched following ice cover development in the three shallowest lakes (50-110%) through a combination of physical and biogeochemical processes. Early winter increases in As were associated with the exclusion of solutes from the developing ice-cover; and large increases in As were measured once oxygen conditions were depleted to the point of anoxia by mid-winter. The onset of anoxic conditions within the water column was associated with large increases in the concentration of redox sensitive elements in lake waters (As, iron [Fe], and manganese [Mn]), suggesting coupling of As mobility with Fe and Mn cycling. In contrast, there was little difference in Sb concentrations under ice suggesting that Sb mobility was controlled by factors other than Fe and Mn associated redox processes. A survey of 30 lakes in the region during fall (open-water) and late-winter (under-ice) revealed large seasonal differences in surface water As were more common in lakes with a maximum depth <4m. This threshold highlights the importance of winter conditions and links between physical lake properties and biogeochemical processes in the chemical recovery of As-impacted subarctic landscapes. The findings indicate annual remobilization of As from contaminated lake sediments may be inhibiting recovery in small shallow lakes that undergo seasonal transitions in redox state.


Psychological Characteristics and Traits for Finding Benefit From Prostate Cancer: Correlates and Predictors.
Although beginning evidence suggests that the capacity to derive benefit from cancer-associated experiences may be influenced by some individual psychological characteristics and traits, little is known about predictors for finding benefit from prostate cancer. The aim of this study was to explore the correlates and predictors for finding benefit from prostate cancer among a sample of men undergoing androgen deprivation. Pearson correlation and multiple linear regression modeling were performed on data collected in an acute tertiary hospital outpatient setting (N = 209) between July 2011 and December 2013 to determine correlates and predictors for finding benefit from prostate cancer. Multiple linear regression modeling showed that while the 6 predictors of self-reported coping, depression, anxiety, distress, resilience, and hope explained 38% of the variance in finding benefit, coping provided the strongest and statistically significant predictive contribution. Self-reported coping was strongly predictive of finding benefit from prostate cancer, but questions remain about if subtypes of coping strategies can be more or less predictive of finding benefit. Self-reported levels of depression, anxiety, distress, resilience, and hope had a less predictive and nonsignificant role in finding benefit from prostate cancer and raise questions about their function in this subpopulation. The findings suggest that coping strategies can maximize finding benefit from prostate cancer. Knowledge of influential coping strategies for finding benefit from prostate cancer can be immensely valuable to support men in rebuilding positive meaning amid a changed illness reality. Developing practice initiatives that foster positive meaning-making coping strategies seems valuable.