Cu₂Se and Cu Nanocrystals as Local Sources of Copper in Thermally Activated In Situ Cation Exchange.
Among the different synthesis approaches to colloidal nanocrystals, a recently developed toolkit is represented by cation exchange reactions, where the use of template nanocrystals gives access to materials that would be hardly attainable via direct synthesis. Besides, postsynthetic treatments, such as thermally activated solid-state reactions, represent a further flourishing route to promote finely controlled cation exchange. Here, we report that, upon in situ heating in a transmission electron microscope, Cu2Se or Cu nanocrystals deposited on an amorphous solid substrate undergo partial loss of Cu atoms, which are then engaged in local cation exchange reactions with Cu "acceptor" phases represented by rod- and wire-shaped CdSe nanocrystals. This thermal treatment slowly transforms the initial CdSe nanocrystals into Cu(2-x)Se nanocrystals, through the complete sublimation of Cd and the partial sublimation of Se atoms. Both Cu "donor" and "acceptor" particles were not always in direct contact with each other; hence, the gradual transfer of Cu species from Cu2Se or metallic Cu to CdSe nanocrystals was mediated by the substrate and depended on the distance between the donor and acceptor nanostructures. Differently from what happens in the comparably faster cation exchange reactions performed in liquid solution, this study shows that slow cation exchange reactions can be performed at the solid state and helps to shed light on the intermediate steps involved in such reactions.


Possible endocrine control by follistatin 315 during liver regeneration based on changes in the activin receptor after a partial hepatectomy in rats.
Activin A is an autocrine inhibitor of cell growth in the liver. The biological activity of activin A is mediated by a heteromeric receptor complex. Follistatin (FS) binds to activin and inhibits its biological effects, and acts as a negative regulator of muscle cells. The role of activin receptors during liver regeneration following a hepatectomy has not been fully assessed. This study investigates the mechanism underlying how activin receptors regulate hepatocyte growth, and the effects of intravenous administration of FS during liver regeneration. The expression of both activins and activin receptors in the liver after a 70% partial hepatectomy (HT) was assessed by RT-PCR and immunohistochemistry. FS 315 or 288 was infused for different periods of time based on changes in hepatocyte activin receptor expression after HT. Activin receptor expression peaked between 48 and 72 hours after HT. 72 hours after HT, an injection of FS 315 resulted in a more potent stimulation of DNA synthesis and produced a greater increase in body weight compared with the control rats. The expression of activin receptors after peak DNA synthesis might be a key component in the downregulation of DNA synthesis. Intravenous administration of FS 315 might promote liver regeneration and have anabolic actions.


Reconstructing transmission trees for communicable diseases using densely sampled genetic data.
Whole genome sequencing of pathogens from multiple hosts in an epidemic offers the potential to investigate who infected whom with unparalleled resolution, potentially yielding important insights into disease dynamics and the impact of control measures. We considered disease outbreaks in a setting with dense genomic sampling, and formulated stochastic epidemic models to investigate person-to-person transmission, based on observed genomic and epidemiological data. We constructed models in which the genetic distance between sampled genotypes depends on the epidemiological relationship between the hosts. A data augmented Markov chain Monte Carlo algorithm was used to sample over the transmission trees, providing a posterior probability for any given transmission route. We investigated the predictive performance of our methodology using simulated data, demonstrating high sensitivity and specificity, particularly for rapidly mutating pathogens with low transmissibility. We then analyzed data collected during an outbreak of methicillin-resistant Staphylococcus aureus in a hospital, identifying probable transmission routes and estimating epidemiological parameters. Our approach overcomes limitations of previous methods, providing a framework with the flexibility to allow for unobserved infection times, multiple independent introductions of the pathogen, and within-host genetic diversity, as well as allowing forward simulation.


Bile-induced peptidoglycan remodelling in Salmonella enterica.
Changes in the peptidoglycan (PG) structure of Salmonella enterica are detected in the presence of a sublethal concentration of sodium deoxycholate (DOC): (i) lower proportions of Braun lipoprotein (Lpp)-bound muropeptides; (ii) reduced levels of muropeptides cross-linked by L(meso)-diaminopimelyl-D(meso)-diaminopimelic acid (L-D) peptide bridges (3-3 cross-links). Similar structural changes are found in S. enterica cultures adapted to grow in the presence of a lethal concentration of DOC, suggesting that reduced anchoring of Braun protein to PG and low occurrence of 3-3 cross-links may increase S. enterica resistance to bile. This view is further supported by additional observations: (i) A triple mutant lacking L,D-transpeptidases YbiS, ErfK, and YcfS, which does not contain Lpp anchored to PG, is hyper-resistant to bile; (ii) enhanced 3-3 cross-linking upon overexpression of YnhG transpeptidase causes a decrease in bile resistance. These observations suggest that remodelling of the cell wall may be added to the list of adaptive responses that permit survival of S. enterica in the presence of bile.


Phase extension in crystallography using the iterative Fienup-Gerchberg-Saxton algorithm and Hilbert transforms.
A procedure for phase extension in electron crystallography is proposed based on the iterative Fienup-Gerchberg-Saxton algorithm in combination with the use of discrete Hilbert transforms. This transform is used to provide oversampling in reciprocal space, thus satisfying the Shannon sampling requirement and introducing reflections with fractional indices. When the procedure is combined with the knowledge of a small set of strong phased Bragg reflections from electron-microscope images (or direct methods), the magnitudes of many non-Bragg reflections can be calculated with useful accuracy, thus enhancing the performance of the iterative algorithm for phase extension. The effects of various constraints used in the iterative algorithm are discussed. In this way, it is shown that the iterative algorithm conventionally used for phasing diffuse scattering from non-periodic objects can also be applied to problems in conventional crystallography to find the phases of high-order (resolution) beams from a known set of low-order (resolution) phases.


Regulation of histone H4 Lys16 acetylation by predicted alternative secondary structures in roX noncoding RNAs.
Despite differences in size and sequence, the two noncoding roX1 and roX2 RNAs are functionally redundant for dosage compensation of the Drosophila melanogaster male X chromosome. Consistent with functional conservation, we found that roX RNAs of distant Drosophila species could complement D. melanogaster roX mutants despite low homology. Deletion of a conserved predicted stem-loop structure in roX2, containing a short GUb (GUUNUACG box) in its 3' stem, resulted in a defect in histone H4K16 acetylation on the X chromosome in spite of apparently normal localization of the MSL complex. Two copies of the GUb sequence, newly termed the "roX box," were functionally redundant in roX2, as mutants in a single roX box had no phenotype, but double mutants showed reduced H4K16 acetylation. Interestingly, mutation of two of three roX boxes in the 3' end of roX1 RNA also reduced H4K16 acetylation. Finally, fusion of roX1 sequences containing a roX box restored function to a roX2 deletion RNA lacking its cognate roX box. These results support a model in which the functional redundancy between roX1 and roX2 RNAs is based, at least in part, on short GUUNUACG sequences that regulate the activity of the MSL complex.


ReStNeuMap: a tool for automatic extraction of resting-state functional MRI networks in neurosurgical practice.
Resting-state functional MRI (rs-fMRI) represents a promising and cost-effective alternative to task-based fMRI for presurgical mapping. However, the lack of clinically streamlined and reliable rs-fMRI analysis tools has prevented wide adoption of this technique. In this work, the authors introduce an rs-fMRI processing pipeline (ReStNeuMap) for automatic single-patient rs-fMRI network analysis. The authors provide a description of the rs-fMRI network analysis steps implemented in ReStNeuMap and report their initial experience with this tool after performing presurgical mapping in 6 patients. They verified the spatial agreement between rs-fMRI networks derived by ReStNeuMap and localization of activation with intraoperative direct electrical stimulation (DES). The authors automatically extracted rs-fMRI networks including eloquent cortex in spatial proximity with the resected lesion in all patients. The distance between DES points and corresponding rs-fMRI networks was less than 1 cm in 78% of cases for motor, 100% of cases for visual, 87.5% of cases for language, and 100% of cases for speech articulation mapping. The authors' initial experience with ReStNeuMap showed good spatial agreement between presurgical rs-fMRI predictions and DES findings during awake surgery. The availability of the rs-fMRI analysis tools for clinicians aiming to perform noninvasive mapping of brain functional networks may extend its application beyond surgical practice.


Does information matter? Competition, quality, and the impact of nursing home report cards.
We evaluate the effects of the Nursing Home Quality Initiative (NHQI), which introduced quality measures to the Centers for Medicare and Medicaid Services' Nursing Home Compare website, on facility performance and consumer demand for services. The nursing home Minimum Data Set facility reports from 1999 to 2005 merged with facility-level data from the On-Line Survey, Certification, and Reporting System. We rely on the staggered rollout of the report cards across pilot and nonpilot states to examine the effect of report cards on market share and quality of care. We also exploit differences in nursing home market competition at baseline to identify the impacts of the new information on nursing home quality. The introduction of the NHQI was generally unrelated to facility quality and consumer demand. However, nursing homes facing greater competition improved their quality more than facilities in less competitive markets. The lack of competition in many nursing home markets may help to explain why the NHQI report card effort had a minimal effect on nursing home quality. With the introduction of market-based reforms such as report cards, this result suggests policy makers must also consider market structure in efforts to improve nursing home performance.


Systematic repression of transcription factors reveals limited patterns of gene expression changes in ES cells.
Networks of transcription factors (TFs) are thought to determine and maintain the identity of cells. Here we systematically repressed each of 100 TFs with shRNA and carried out global gene expression profiling in mouse embryonic stem (ES) cells. Unexpectedly, only the repression of a handful of TFs significantly affected transcriptomes, which changed in two directions/trajectories: one trajectory by the repression of either Pou5f1 or Sox2; the other trajectory by the repression of either Esrrb, Sall4, Nanog, or Tcfap4. The data suggest that the trajectories of gene expression change are already preconfigured by the gene regulatory network and roughly correspond to extraembryonic and embryonic fates of cell differentiation, respectively. These data also indicate the robustness of the pluripotency gene network, as the transient repression of most TFs did not alter the transcriptomes.


SNAFU: The Semantic Network and Fluency Utility.
The verbal fluency task-listing words from a category or words that begin with a specific letter-is a common experimental paradigm that is used to diagnose memory impairments and to understand how we store and retrieve knowledge. Data from the verbal fluency task are analyzed in many different ways, often requiring manual coding that is time intensive and error-prone. Researchers have also used fluency data from groups or individuals to estimate semantic networks-latent representations of semantic memory that describe the relations between concepts-that further our understanding of how knowledge is encoded. However computational methods used to estimate networks are not standardized and can be difficult to implement, which has hindered widespread adoption. We present SNAFU: the Semantic Network and Fluency Utility, a tool for estimating networks from fluency data and automatizing traditional fluency analyses, including counting cluster switches and cluster sizes, intrusions, perseverations, and word frequencies. In this manuscript, we provide a primer on using the tool, illustrate its application by creating a semantic network for foods, and validate the tool by comparing results to trained human coders using multiple datasets.


Both comprehensive and brief self-administered diet history questionnaires satisfactorily rank nutrient intakes in Japanese adults.
A comprehensive self-administered diet history questionnaire (DHQ: 150-item semi-quantitative questionnaire) and a brief self-administered DHQ (BDHQ: 58-item fixed-portion-type questionnaire) were developed for assessing Japanese diets. We compared the relative validity of nutrient intake derived from DHQ with that from the BDHQ, using semi-weighed 16-day dietary records (DRs) as reference. Ninety-two Japanese women aged 31 to 69 years and 92 Japanese men aged 32 to 76 years completed a 4-nonconsecutive-day DR, a DHQ, and a BDHQ 4 times each (once per season) in 3 areas of Japan (Osaka, Nagano, and Tottori). No significant differences were seen in estimates of energy-adjusted intakes of 42 selected nutrients (based on the residual method) between the 16-day DRs and the first DHQ (DHQ1) or between the DR and the first BDHQ (BDHQ1) for 18 (43%) and 14 (33%) nutrients, respectively, among women and for 4 (10%) and 21 (50%) nutrients among men. The median (interquartile range) Pearson correlation coefficients with the DR for energy-adjusted intakes of the 42 nutrients were 0.57 (0.50 to 0.64) for the DHQ1 and 0.54 (0.45 to 0.61) for the BDHQ1 in women; in men, the respective values were 0.50 (0.42 to 0.59) and 0.56 (0.41 to 0.63). Similar results were observed for the means of the 4 DHQs and BDHQs. The DHQ and BDHQ had satisfactory ranking ability for the energy-adjusted intakes of many nutrients among the present Japanese population, although these instruments were satisfactory in estimating mean values for only a small number of nutrients.


Body Piercing: A National Survey in France.
There are no recent data available in France regarding body piercing (BP). We examined the demographics, motivations, quality of life, cutaneous conditions, and cutaneous side effects after BP within the French population. A representative sample of 5,000 individuals (aged 15 and over) from the general population responded to a survey online between April and August 2017. Data regarding demographics, BP characteristics (location, age at first piercing, hesitation, regrets, motivations, cutaneous side effects), tobacco, skin conditions (acne, contact eczema, atopic eczema, rosacea, psoriasis, vitiligo), and tattoos were collected. Respondents also filled an SF-12 quality of life questionnaire. Overall, 12% of the respondents reported at least one BP (women: 19.4%, men: 8.4%, p < 0.01). The prevalence was highest among those aged between 25 and 34 years (25.8%). Individuals with BP were more likely to smoke (p < 0.01). The most common body parts for piercings were the external part of the ear (42%), the navel (24%), the tongue (15%), and the nose (11%). Gender differences included localization (belly button and nose for women, eyebrows for men) and motivations (embellishment of the body for women, individuality and sexuality for men). A total of 33.6% of the study participants reported having skin problems after BP, primarily infection (44%). Individuals with BPs were more likely to report having contact eczema, atopic dermatitis, and acne. BP was associated with a lower mental quality of life score. This is the largest epidemiological study on BP in France to date. It allows us to draw a precise current snapshot of French indi viduals with BP.


Doom and boom on a resilient reef: climate change, algal overgrowth and coral recovery.
Coral reefs around the world are experiencing large-scale degradation, largely due to global climate change, overfishing, diseases and eutrophication. Climate change models suggest increasing frequency and severity of warming-induced coral bleaching events, with consequent increases in coral mortality and algal overgrowth. Critically, the recovery of damaged reefs will depend on the reversibility of seaweed blooms, generally considered to depend on grazing of the seaweed, and replenishment of corals by larvae that successfully recruit to damaged reefs. These processes usually take years to decades to bring a reef back to coral dominance. In 2006, mass bleaching of corals on inshore reefs of the Great Barrier Reef caused high coral mortality. Here we show that this coral mortality was followed by an unprecedented bloom of a single species of unpalatable seaweed (Lobophora variegata), colonizing dead coral skeletons, but that corals on these reefs recovered dramatically, in less than a year. Unexpectedly, this rapid reversal did not involve reestablishment of corals by recruitment of coral larvae, as often assumed, but depended on several ecological mechanisms previously underestimated. These mechanisms of ecological recovery included rapid regeneration rates of remnant coral tissue, very high competitive ability of the corals allowing them to out-compete the seaweed, a natural seasonal decline in the particular species of dominant seaweed, and an effective marine protected area system. Our study provides a key example of the doom and boom of a highly resilient reef, and new insights into the variability and mechanisms of reef resilience under rapid climate change.


Reduction of thermal conductivity in silicene nanomesh: insights from coherent and incoherent phonon transport.
Silicene nanomesh (SNM), a silicene sheet with periodically arranged nanoholes, has gained increasing interest due to its unique geometry and novel properties. In this paper, we have conducted molecular dynamics simulations to study the phonon transport properties of SNMs. The results demonstrate that the thermal conductivity of SNM, which is shown to be much lower than that of silicene, is little affected by temperature but can be effectively tuned by varying the porosity. To elucidate the underlying mechanisms for decreased thermal conductivity, we have investigated both coherent and incoherent phonon transport in SNMs. It is found that the phonon backscattering at the nanopore edges leads to extra thermal resistances. Additionally, the introduction of nanopores induces phonon localization and consequently hinders phonon transport in SNMs. The phonons of SNM exhibit coherent resonant behavior, which is believed to reduce the phonon group velocities and thus leads to a further reduction in thermal conductivity of SNMs. Our findings could be useful in the design of thermal properties of silicene for applications in thermoelectrics, thermal insulation and thermal protection.


Comparative genomic sequence analysis and isolation of human and mouse alternative EGFR transcripts encoding truncated receptor isoforms.
This study presents the annotated genomic sequence and exon-intron organization of the human and mouse epidermal growth factor receptor (EGFR) genes located on chromosomes 7p11.2 and 11, respectively. We report that the EGFR gene spans nearly 200 kb and that the full-length 170-kDa EGFR is encoded by 28 exons. In addition, we have identified two human and two mouse alternative EGFR transcripts of 2.4-3.0 kb using both computational and experimental methods. The human 3.0-kb and mouse 2.8-kb EGFR mRNAs are predominantly expressed in placenta and liver, respectively, and both transcripts encode 110-kDa truncated receptor isoforms containing only the extracellular ligand-binding domain. We also have demonstrated that the aberrant 2.8-kb EGFR transcript produced by the human A431 carcinoma cell line is generated by splicing to a recombinant 3'-terminal exon located in EGFR intron 16, which apparently was formed as a result of a chromosomal translocation. Finally, we have shown that the human, mouse, rat, and chicken 1.8- to 3.0-kb alternative EGFR transcripts are generated by distinct splicing mechanisms and that each of these mRNAs contains unique 3' sequences that are not evolutionarily conserved. The presence of truncated receptor isoforms in diverse species suggests that these proteins may have important functional roles in regulating EGFR activity.


Development of the 21-gene assay and its application in clinical practice and clinical trials.
Several multigene markers that predict relapse more accurately than classical clinicopathologic features have been developed. The 21-gene assay was developed specifically for patients with estrogen receptor (ER)-positive breast cancer, and has been shown to predict distant recurrence more accurately that classical clinicopathologic features in patients with ER-positive breast cancer and negative axillary nodes treated with adjuvant tamoxifen; validation studies in this population led to its approval as a diagnostic test. In a similar population, it also may be used to assess the benefit of adding chemotherapy to hormonal therapy. Other validation studies indicate that it also predicts the risk of distant and local recurrence in other populations with ER-positive disease, including node-negative patients receiving no adjuvant therapy and patients with positive axillary nodes treated with doxorubicin-containing chemotherapy. The Trial Assigning Individualized Options for Treatment (TAILORx) is multicenter trial that integrates the 21-gene assay into the clinical decision-making process and is designed to refine the utility of the assay in clinical practice and to provide a resource for evaluating additional molecular markers as they are developed in the future.


The North-South gap in overweight and obesity in England.
Regional differences in overweight and obesity levels in England have mirrored those of CVD, with higher levels in the North. It is unclear whether the increase in the prevalence of overweight and obesity over the last 15 years has been consistent in different regions of the country. BMI data from each of the health surveys for England conducted between 1993 and 2004 were analysed. Annual grouped estimates of the prevalence of overweight (BMI >/= 25 kg/m2) and obesity (BMI >/= 30 kg/m2) for the North and the South of England were produced by appropriately combining regional administrative authorities. Logistic regression analyses were performed to assess the independence of the geographical effect after adjustment for age and social class. The prevalence of both overweight and obesity in women has risen more quickly in the North than in the South between 1993 and 2004, leading to a widening of inequalities. The prevalence of both overweight and obesity in women in the South has remained reasonably stable since 1997. The prevalence rates of both conditions in men have risen in parallel in the North and the South between 1993 and 2004 by approximately 8 %. The OR for obesity for young women increased between 1993/98 and 1998/2004 from 1.07 (1.00, 1.14) to 1.21 (1.13, 1.30). Widening geographical inequalities in overweight and obesity rates in women could lead to widening inequalities in cardiovascular and other diseases.


The association between physical dependency and the presence of neuropsychiatric symptoms, with the admission of people with dementia to a long-term care institution: a prospective observational cohort study.
Dementia is a progressive neurological disorder that causes a high degree of dependency. This dependency has been defined as an increased need for assistance due to deterioration in cognition and physical functioning, and changes in behavior. Highly dependent people with dementia are more likely to be institutionalized. To investigate the association between specific categories of physical dependency and the presence of neuropsychiatric symptoms in people with dementia admitted to a long-term care institution. A prospective observational cohort study. Home care and long-term care institutions in eight European countries. People with dementia living at home but at risk of institutionalization and recently institutionalized people with dementia. Baseline and 3-month follow-up interviews were performed between November, 2010 and April, 2012. The sample consisted of 116 recently institutionalized dementia sufferers and 949 people with dementia still living at home. Physical dependency was measured using the Katz Activity of Daily Living index, and neuropsychiatric symptoms were assessed through The Neuropsychiatric Inventory. Specific categories of dependency were analyzed by performing a logistic regression analysis. This followed examination of baseline characteristics to define the degree of physical dependency, as factors associated with institutionalization, and evaluation of the same characteristics at 3-month follow-up to detect changes in the degree of physical dependency and neuropsychiatric symptoms associated with recent admission to a long-term care institution. Toileting, dressing and continence dependency was higher in institutionalized people than in those receiving home-care. Delusion, hallucination, agitation, anxiety, apathy, motor-disturbances, night-time behavior and eating disorders were also worse in the institutionalized. Logistic regression analysis showed that independent factors significantly associated with being recently institutionalized were toileting (odds ratio=2.3; 95% confidence interval=1.43-3.71) and motor disturbances (odds ratio=1.81; 95% confidence interval=1.15-2.87). This study supports the association between type and degree of physical dependency in people with dementia and long-term institutionalization. Institutionalization is associated with physical dependency and the presence of neuropsychiatric symptoms.


[Senior citizen's physical activity and welfare].
This work analysed senior citizens' perception of needs and social values involved in taking physical activity for their own benefit. This study's main aim was to investigate social representations of 3rd age physical activity. This was a cross-sectional, interdisciplinary qualitative study, underpinned by theoretical-methodological social representation theory. A convenience, non-probabilistic, census-dependent method was used for obtaining the sam-ple of 62 people aged 50 to 78 from north-eastern Brazil. The data were collected by using the free word association technique and analysed by EVOC/2000 software. Analysing the replies led to three types of elements being identified which were related to the social representation of physical activity as attributed by the elderly: a psychological dimension (represented by happiness, well-being), a social dimension (dancing) and a biophysical dimension (gymnastics, water-gymnastics and health). The term 'happiness' stood out most in the word recall tests. When relating old age to the sample's social representation of physical activity, the study showed that physical activity assumed a preponderant role in the life of the elderly through cyclical appreciation-depreciation, social representation simultaneously and gradually acquiring 'life having more health and quality' from social representation. The subjects reported a positive association between physical activity, social interaction and well-being. The elderly also believed in physical activity's effects on physical-motor aspects and health. The social representation of physical activity by the group being studied was close to the physical activity's biopsychosocial dimension.


National observational study to evaluate the "cleanyourhands" campaign (NOSEC): a questionnaire based study of national implementation.
The number of national hand-hygiene campaigns has increased recently, following the World Health Organisation's (WHO) "Save Lives: clean your hands" initiative (2009), which offers hospitals a multi-component hand-hygiene intervention. The number of campaigns to be evaluated remains small. Most evaluations focus on consumption of alcohol hand rub (AHR). We are not aware of any evaluation reporting implementation of all campaign components. In a previously published report, we evaluated the effects of the English and Welsh cleanyourhands campaign (2004-8) on procurement of AHR and soap, and on selected healthcare associated infections. We now report on the implementation of each individual campaign component: provision of bedside AHR, ward posters, patient empowerment materials, audit and feedback, and guidance to secure institutional engagement. all 189 acute National Health Service (NHS) hospitals in England and Wales (December 2005-June 2008). Six postal questionnaires (five voluntary, one mandatory) were distributed to infection control teams six-monthly from 6 to 36 months post roll-out. Selection and attrition bias were measured. Response rates fell from 134 (71 %) at 6 months to 82 (44 %) at 30 months, rising to 167 (90 %) for the final mandatory one (36 months). There was no evidence of attrition or selection bias. Hospitals reported widespread early implementation of bedside AHR and posters and a gradual rise in audit. At 36 months, 90 % of respondents reported the campaign to be a top hospital priority, with implementation of AHR, posters and audit reported by 96 %, 97 % and 91 % respectively. Patient empowerment was less successful. The study suggests that all campaign components, apart from patient empowerment, were widely implemented and sustained. It supports previous work suggesting that adequate piloting, strong governmental support, refreshment of campaigns, and sufficient time to engage institutions help secure sustained implementation of a campaign's key components. The results should encourage countries wishing to launch coordinated national campaigns for hospitals to participate in the WHO's "Save Lives" initiative, which offers hospitals a similar multi-component intervention.


Sugar industry sponsorship of germ-free rodent studies linking sucrose to hyperlipidemia and cancer: An historical analysis of internal documents.
In 1965, the Sugar Research Foundation (SRF) secretly funded a review in the New England Journal of Medicine that discounted evidence linking sucrose consumption to blood lipid levels and hence coronary heart disease (CHD). SRF subsequently funded animal research to evaluate sucrose's CHD risks. The objective of this study was to examine the planning, funding, and internal evaluation of an SRF-funded research project titled "Project 259: Dietary Carbohydrate and Blood Lipids in Germ-Free Rats," led by Dr. W.F.R. Pover at the University of Birmingham, Birmingham, United Kingdom, between 1967 and 1971. A narrative case study method was used to assess SRF Project 259 from 1967 to 1971 based on sugar industry internal documents. Project 259 found a statistically significant decrease in serum triglycerides in germ-free rats fed a high sugar diet compared to conventional rats fed a basic PRM diet (a pelleted diet containing cereal meals, soybean meals, whitefish meal, and dried yeast, fortified with a balanced vitamin supplement and trace element mixture). The results suggested to SRF that gut microbiota have a causal role in carbohydrate-induced hypertriglyceridemia. A study comparing conventional rats fed a high-sugar diet to those fed a high-starch diet suggested that sucrose consumption might be associated with elevated levels of beta-glucuronidase, an enzyme previously associated with bladder cancer in humans. SRF terminated Project 259 without publishing the results. The sugar industry did not disclose evidence of harm from animal studies that would have (1) strengthened the case that the CHD risk of sucrose is greater than starch and (2) caused sucrose to be scrutinized as a potential carcinogen. The influence of the gut microbiota in the differential effects of sucrose and starch on blood lipids, as well as the influence of carbohydrate quality on beta-glucuronidase and cancer activity, deserve further scrutiny.


Mortality among 5-17 year old children in Kenya.
Global mortality trends have changed over time and are expected to continue changing with a reduction in communicable diseases and an increase of non-communicable disease. Increased survival of children beyond five years may change mortality patterns for these children. There are few studies in Africa that explore the causes of mortality in children over five years. The objective of this study was to determine the mortality rate and clinical profiles of children aged 5-17 years who died in six Kenyan hospitals in 2013. Retrospective review of patients' medical records to abstract data on diagnosis for those who died in year 2013. Data was analysed to provide descriptive statistics and explored differences in mortality rates between age groups and gender. We retrieved 4,520 patient records. The in-hospital mortality rate was 3.5% (95%CI 3.0-4.1) with variations in deaths between the ages and gender. Among the deaths, 60% suffered from communicable diseases, maternal and nutritional causes; 41.3% suffered from non-communicable diseases. A further 11.9% succumbed to traumatic injuries. The predominant clinical diagnoses among patients who died were HIV/AIDS, respiratory tract infections and malaria. Infectious causes had the highest proportion of diagnoses among children aged 5-17 years who died.


Ethical issues when modelling brain disorders innon-human primates.
Non-human animal models of human diseases advance our knowledge of the genetic underpinnings of disease and lead to the development of novel therapies for humans. While mice are the most common model organisms, their usefulness is limited. Larger animals may provide more accurate and valuable disease models, but it has, until recently, been challenging to create large animal disease models. Genome editors, such as Clustered Randomised Interspersed Palindromic Repeat (CRISPR), meet some of these challenges and bring routine genome engineering of larger animals and non-human primates (NHPs) well within reach. There is growing interest in creating NHP models of brain disorders such as autism, depression and Alzheimer's, which are very difficult to model or study in other organisms, including humans. New treatments are desperately needed for this set of disorders. This paper is novel in asking: Insofar as NHPs are being considered for use as model organisms for brain disorders, can this be done ethically? The paper concludes that it cannot. Notwithstanding ongoing debate about NHPs' moral status, (1) animal welfare concerns, (2) the availability of alternative methods of studying brain disorders and (3) unmet expectations of benefit justify a stop on the creation of NHP model organisms to study brain disorders. The lure of using new genetic technologies combined with the promise of novel therapeutics presents a formidable challenge to those who call for slow, careful, and only necessary research involving NHPs. But researchers should not create macaques with social deficits or capuchin monkeys with memory deficits just because they can.


Cultural awareness in veterinary practice: student perceptions.
Australian veterinary classrooms are increasingly diverse and their growing internal diversity is a result of migration and large numbers of international students. Graduates interact with other students and increasingly with clients whose attitudes, beliefs, values, and behaviors differ from their own. An understanding and respect for these differences has an impact on client communication and health care outcomes. The present study explored how students understand and are likely to deal with issues of cultural diversity in veterinary professional practice as well as the educational needs that students feel should be met in regard to preparation to engage productively with diversity in professional practice. The present study also explored the extent to which the rich diversity of the undergraduate student population constitutes an educational resource. A class of final-year veterinary students was invited to participate in a workshop exploring intercultural confidence in veterinary consultation. Twelve groups of six to eight students discussed a fictitious scenario involving a challenging clinical encounter with a client from a different culture. Students were reticent to see the scenario in terms of cultural difference, although they generally recognized that awareness of cultural issues in veterinary practice was important. They also tended to not see their own ethnicity as relevant to their practice. While some felt that veterinary practice should be culture blind, most recognized a need to orient to cultural difference and to respond sensitively. Their suggestions for curricular improvements to address these issues are also included.


Mammalian SEPT9 isoforms direct microtubule-dependent arrangements of septin core heteromers.
Septin-family proteins assemble into rod-shaped heteromeric complexes that form higher-order arrangements at the cell cortex, where they serve apparently conserved functions as diffusion barriers and molecular scaffolds. There are 13 confirmed septin paralogues in mammals, which may be ubiquitous or tissue specific. Septin hetero-oligomerization appears homology subgroup directed, which in turn determines the subunit arrangement of six- to eight-subunit core heteromers. Here we address functional properties of human SEPT9, which, due to variable mRNA splicing, exists as multiple isoforms that differ between tissues. Myeloid K562 cells express three SEPT9 isoforms, all of which have an equal propensity to hetero-oligomerize with SEPT7-containing hexamers to generate octameric heteromers. However, due to limiting amounts of SEPT9, K562 cells contain both hexameric and octameric heteromers. To generate cell lines with controllable hexamer-to-octamer ratios and that express single SEPT9 isoforms, we developed a gene product replacement strategy. By this means we identified SEPT9 isoform-specific properties that either facilitate septin heteromer polymerization along microtubules or modulate the size range of submembranous septin disks-a prevalent septin structure in nonadhered cells. Our findings show that the SEPT9 expression level directs the hexamer-to-octamer ratio, and that the isoform composition and expression level together determine higher-order arrangements of septins.


The effect of hard tissue surgical changes on soft tissue displacement: a pilot CBCT study.
This pilot study had as main objective to test the reliability of a new method to evaluate orthognathic surgery outcomes and also, to understand the effect of hard tissue changes on soft tissue displacement. The sample consisted of eight patients that underwent bimaxillary advancement and had CBCT at two time points (before surgery and 6-8 months follow-up). Voxel-based cranial base superimposition was used to register the scans. A different technique of iterative closest point (ICP) was used to measure and correlate the changes. The average displacement of 15 areas (4 hard tissue and 11 soft tissue) were measured twice. ICC was > 0.99 for all areas. Changes in the tip of the nose did not correlate with changes in any maxillary area, whereas soft tissue A point, A point and upper lips had correlation with several areas. The highest correlation for the maxilla was between the upper lip and the left/right supra cheilion (p< 0.001, r= 0.91 and p< 0.001, r= 0.93, respectively). In the mandible, the majority of the correlations involved soft tissue pogonion, pogonion and lower incisors, with the strongest one between pogonion and lower incisors (p< 0.001, r= 0.98). With the proper case selection, ICP is a reliable method that can be used to assess three-dimensional changes.


Role of cation-pi interactions to the stability of thermophilic proteins.
Elucidating the factors responsible for exhibiting extreme thermal stability of thermophilic proteins is very important for an understanding of the mechanism of protein stability, as well as to design stable proteins. In this work, we have analyzed the influence of cation-pi interactions to enhance the stability from mesophilic to thermophilic proteins. The favorable residue pairs forming such a system of interactions have been brought out. We found that the Tyr has a greater number of such interactions with Lys in thermophilic proteins. Specifically, the same Lys would experience a greater number of cation-pi interactions with several Tyr residues in thermophiles. On the other hand, the influence of Phe in making cation-pi interactions is higher in mesophiles than in thermophiles. Further, a network of cation-pi interactions are maintained by Lys in thermophiles, whereas Arg plays a major role in mesophilic proteins. Moreover, atoms that have a substantial positive charge in both Lys and Arg make a more significant contribution for cation-pi interactions than do cationic group atoms.


The effects of a rise in cigarette price on cigarette consumption, tobacco taxation revenues, and of smoking-related deaths in 28 EU countries-- applying threshold regression modelling.
European Union public healthcare expenditure on treating smoking and attributable diseases is estimated at over €25bn annually. The reduction of tobacco consumption has thus become one of the major social policies of the EU. This study investigates the effects of price hikes on cigarette consumption, tobacco tax revenues and smoking-caused deaths in 28 EU countries. Employing panel data for the years 2005 to 2014 from Euromonitor International, the World Bank and the World Health Organization, we used income as a threshold variable and applied threshold regression modelling to estimate the elasticity of cigarette prices and to simulate the effect of price fluctuations. The results showed that there was an income threshold effect on cigarette prices in the 28 EU countries that had a gross national income (GNI) per capita lower than US$5418, with a maximum cigarette price elasticity of -1.227. The results of the simulated analysis showed that a rise of 10% in cigarette price would significantly reduce cigarette consumption as well the total death toll caused by smoking in all the observed countries, but would be most effective in Bulgaria and Romania, followed by Latvia and Poland. Additionally, an increase in the number of MPOWER tobacco control policies at the highest level of achievment would help reduce cigarette consumption. It is recommended that all EU countries levy higher tobacco taxes to increase cigarette prices, and thus in effect reduce cigarette consumption. The subsequent increase in tobacco tax revenues would be instrumental in covering expenditures related to tobacco prevention and control programs.


Development and characterization of polymorphic EST-SSR and genomic SSR markers for Tibetan annual wild barley.
Tibetan annual wild barley is rich in genetic variation. This study was aimed at the exploitation of new SSRs for the genetic diversity and phylogenetic analysis of wild barley by data mining. We developed 49 novel EST-SSRs and confirmed 20 genomic SSRs for 80 Tibetan annual wild barley and 16 cultivated barley accessions. A total of 213 alleles were generated from 69 loci with an average of 3.14 alleles per locus. The trimeric repeats were the most abundant motifs (40.82%) among the EST-SSRs, while the majority of the genomic SSRs were di-nuleotide repeats. The polymorphic information content (PIC) ranged from 0.08 to 0.75 with a mean of 0.46. Besides this, the expected heterozygosity (He) ranged from 0.0854 to 0.7842 with an average of 0.5279. Overall, the polymorphism of genomic SSRs was higher than that of EST-SSRs. Furthermore, the number of alleles and the PIC of wild barley were both higher than that of cultivated barley, being 3.12 vs 2.59 and 0.44 vs 0.37. Indicating more polymorphism existed in the Tibetan wild barley than in cultivated barley. The 96 accessions were divided into eight subpopulations based on 69 SSR markers, and the cultivated genotypes can be clearly separated from wild barleys. A total of 47 SSR-containing EST unigenes showed significant similarities to the known genes. These EST-SSR markers have potential for application in germplasm appraisal, genetic diversity and population structure analysis, facilitating marker-assisted breeding and crop improvement in barley.


Modest and uneven: physician efforts to reduce racial and ethnic disparities.
While nearly half of U. S. physicians identify language or cultural communication barriers as obstacles to providing high-quality care, physician adoption of practices to overcome such barriers is modest and uneven, according to a new national study by the Center for Studying Health System Change (HSC). Despite broad consensus among the medical community about how physicians can help to address and, ultimately, reduce racial and ethnic disparities, physician adoption of several recommended practices to improve care for minority patients ranges from 7 percent reporting they have the capability to track patients' preferred language to 40 percent reporting they have received training in minority health issues to slightly more than half reporting their practices provide some interpreter services. The challenges physicians face in providing quality health care to all of their patients will keep mounting as the U.S. population continues to diversify and the minority population increases


B cells are crucial for both development and maintenance of the splenic marginal zone.
The splenic marginal zone is a unique compartment that separates the lymphoid white pulp from the surrounding red pulp. Due to the orchestration of specialized macrophages and B cells flanking a marginal sinus, this compartment plays an important role in uptake of blood-borne Ags and it gives the spleen its specialized function in antibacterial immunity. In this study, we demonstrate that both development and maintenance of this marginal zone is highly dependent on the presence of B cells. Spleens from B cell-deficient mice were found to lack both metallophilic and marginal zone macrophages as well as mucosal addressin cellular adhesion molecule-1+ sinus lining cells. Using an inducible Cre/loxP-driven mouse model in which mature B cells could be partially depleted by removal of the B cell receptor subunit Igalpha, we could show that the integrity and function of an established marginal zone was also dependent on the presence of B cells. This was confirmed in a transgenic model in which all B cells were gradually depleted due to overexpression of the TNF family member CD70. The loss of all cellular subsets from the marginal zone in these CD70 transgenic mice was effectively prevented by crossing these mice on a CD27(-/-) or TCRalpha(-/-) background, because this prohibited the ongoing B cell depletion. Therefore, we conclude that B cells are not only important for the development, but also for maintenance, of the marginal zone. This direct correlation between circulating B cells and the function of the spleen implies an increased risk for B cell lymphopenic patients with bacterial infections.


Sleep duration, restfulness, and screens in the sleep environment.
Associations of inadequate sleep with numerous health outcomes among youth necessitate identifying its modifiable determinants. Television (TV) has been associated with sleep curtailment, but little is known about small screens (eg, smartphones), which can be used in bed and emit notifications. Therefore, we examined associations of different screens in sleep environments with sleep duration and perceived insufficient rest or sleep. Participants included 2048 fourth- and seventh-graders participating in the Massachusetts Childhood Obesity Research Demonstration Study in 2012 to 2013. Using linear and log binomial regression, we examined cross-sectional associations of small screens and TVs in sleep environments and screen time with weekday sleep duration and perceived insufficient rest or sleep in the past week. Children who slept near a small screen (compared with never) reported 20.6 fewer minutes of sleep (95% confidence interval [CI], -29.7 to -11.4) and had a higher prevalence of perceived insufficient rest or sleep (prevalence ratio, 1.39; 95% CI, 1.21 to 1.60). Children who slept in a room with a TV (compared with no TV) reported 18.0 fewer minutes of sleep (95% CI, -27.9 to -8.1). TV or DVD viewing and video or computer game playing were associated with both sleep outcomes (P < .01). Some associations were stronger among Hispanic, non-Hispanic black, and older children (P < .05 for heterogeneity). Sleeping near a small screen, sleeping with a TV in the room, and more screen time were associated with shorter sleep durations. Presence of a small screen, but not a TV, in the sleep environment and screen time were associated with perceived insufficient rest or sleep. These findings caution against unrestricted screen access in children's bedrooms.


The importance of dietary polyamines in cell regeneration and growth.
The polyamines putrescine, spermidine and spermine are essential for cell renewal and, therefore, are needed to keep the body healthy. It was previously believed that polyamines are synthesized by every cell in the body when required. However, in the present paper evidence is provided to show that, as in the case of the essential amino acids, the diet can supply sufficient amounts of polyamines to support cell renewal and growth. Systematic analysis of different foods was carried out and from the data obtained, the average daily polyamine consumption of British adults was calculated to be in the range 350-500 mumol/person per d. The major sources of putrescine were fruit, cheese and non-green vegetables. All foods contributed similar amounts of spermidine to the diet, although levels were generally higher in green vegetables. Meat was the richest source of spermine. However, only a part of the polyamines supplied by the diet is available for use by the body. Based on experiments with rats it was established that polyamines were readily taken up from the gut lumen, probably by passive diffusion, and were partly metabolized during the process of absorption. More than 80% of the putrescine was converted to other polyamines and non-polyamine metabolites, mostly to amino acids. The enzyme responsible for controlling the bioavailability of putrescine was diamine oxidase (EC 18.104.22.168). For spermidine and spermine, however, about 70-80% of the intragastrically intubated dose remained in the original form. Considering the limitations on bioavailability (metabolism and conversion), the amounts of polyamines supplied by the average daily diet in Britain should satisfy metabolic requirements.


Production and Characterization of the Intra- and Extracellular Carbohydrates and Polymeric Substances (EPS) of Three Sea-Ice Diatom Species, and Evidence for a Cryoprotective Role for EPS.
Diatoms and their associated extracellular polymeric substances (EPS) are major constituents of the microalgal assemblages present within sea ice. Yields and chemical composition of soluble and cell-associated polysaccharides produced by three sea-ice diatoms, Synedropsis sp., Fragilariopsis curta, and F. cylindrus, were compared. Colloidal carbohydrates (CC) contained heteropolysaccharides rich in mannose, xylose, galactose, and glucose. Synedropsis sp. CC consisted mainly of carbohydrates <8 kDa size, with relatively soluble EPS, compared to high proportions of less-soluble EPS produced by both Fragilariopsis spp. F. curta colloidal EPS contained high concentrations of amino sugars (AS). Both Fragilariopsis species had high yields of hot bicarbonate (HB) soluble EPS, rich in xylose, mannose, galactose, and fucose (and AS in F. cylindrus). All species had frustule-associated EPS rich in glucose-mannose. Nutrient limitation resulted in declines in EPS yields and in glucose content of all EPS fractions. Significant similarities between EPS fractions from cultures and different components of natural EPS from Antarctic sea ice were found. Increased salinity (52) reduced growth, but increased yields of EPS in Fragilariopsis cylindrus. Ice formation was inhibited byF. cylindrus, EPS, and by enhanced EPS content (additional xanthan gum) down to -12°C, with growth rate reduced in the presence of xanthan. Differences in the production and composition of EPS between Synedropsis sp. and Fragilariopsis spp., and the association between EPS, freezing and cell survival, supports the hypothesis that EPS production is a strategy to assist polar ice diatoms to survive the cold and saline conditions present in sea ice.


A perspective on SIDS pathogenesis. the hypotheses: plausibility and evidence.
Several theories of the underlying mechanisms of Sudden Infant Death Syndrome (SIDS) have been proposed. These theories have born relatively narrow beach-head research programs attracting generous research funding sustained for many years at expense to the public purse. This perspective endeavors to critically examine the evidence and bases of these theories and determine their plausibility; and questions whether or not a safe and reasoned hypothesis lies at their foundation. The Opinion sets specific criteria by asking the following questions: 1. Does the hypothesis take into account the key pathological findings in SIDS? 2. Is the hypothesis congruent with the key epidemiological risk factors? 3. Does it link 1 and 2? Falling short of any one of these answers, by inference, would imply insufficient grounds for a sustainable hypothesis. Some of the hypotheses overlap, for instance, notional respiratory failure may encompass apnea, prone sleep position, and asphyxia which may be seen to be linked to co-sleeping. For the purposes of this paper, each element will be assessed on the above criteria.


Association Between Neurological Disorders and Death by Suicide in Denmark.
Neurological disorders have been linked to suicide, but the risk across a broad spectrum of neurological disorders remains to be assessed. To examine whether people with neurological disorders die by suicide more often than other people and to assess for temporal associations. Nationwide, retrospective cohort study on all persons 15 years or older living in Denmark, from 1980 through 2016 (N = 7 300 395). Medical contact for head injury, stroke, epilepsy, polyneuropathy, diseases of myoneural junction, Parkinson disease, multiple sclerosis, central nervous system infections, meningitis, encephalitis, amyotrophic lateral sclerosis, Huntington disease, dementia, intellectual disability, and other brain diseases from 1977 through 2016 (n = 1 248 252). Death by suicide during 1980-2016. Adjusted incidence rate ratio (IRRs) were estimated using Poisson regressions, adjusted for sociodemographics, comorbidity, psychiatric diagnoses, and self-harm. Of the more than 7.3 million individuals observed over 161 935 233 person-years (49.1% males), 35 483 died by suicide (median duration of follow-up, 23.6 years; interquartile range, 10.0-37.0 years; mean age, 51.9 years; SD, 17.9 years). Of those, 77.4% were males, and 14.7% (n = 5141) were diagnosed with a neurological disorder, equivalent to a suicide rate of 44.0 per 100 000 person-years compared with 20.1 per 100 000 person-years among individuals not diagnosed with a neurological disorder. People diagnosed with a neurological disorder had an adjusted IRR of 1.8 (95% CI, 1.7-1.8) compared with those not diagnosed. The excess adjusted IRRs were 4.9 (95% CI, 3.5-6.9) for amyotrophic lateral sclerosis, 4.9 (95% CI, 3.1-7.7) for Huntington disease, 2.2 (95% CI, 1.9-2.6) for multiple sclerosis, 1.7 (95% CI, 1.6-1.7) for head injury, 1.3 (95% CI, 1.2-1.3) for stroke, and 1.7 (95% CI, 1.6-1.8) for epilepsy. The association varied according to time since diagnosis with an adjusted IRR for 1 to 3 months of 3.1 (95% CI, 2.7-3.6) and for 10 or more years, 1.5 (95% CI, 1.4 to 1.6, P < .001). Compared with those who were not diagnosed with a neurological disorder, those with dementia had a lower overall adjusted IRR of 0.8 (95% CI, 0.7-0.9), which was elevated during the first month after diagnosis to 3.0 (95% CI, 1.9-4.6; P < .001). The absolute risk of suicide for people with Huntington disease was 1.6% (95% CI, 1.0%-2.5%). In Denmark from 1980 through 2016, there was a significantly higher rate of suicide among those with a diagnosed neurological disorder than persons not diagnosed with a neurological disorder. However, the absolute risk difference was small.


The Gastrointestinal Tract Is a Major Source of Echinocandin Drug Resistance in a Murine Model of Candida glabrata Colonization and Systemic Dissemination.
Candida species are a part of the human microbiome and can cause systemic infection upon immune suppression. Candida glabrata infections are increasing and have greater rates of antifungal resistance than other species. Here, we present a C. glabrata gastrointestinal (GI) colonization model to explore whether colonized yeast exposed to caspofungin, an echinocandin antifungal, develop characteristic resistance mutations and, upon immunosuppression, breakthrough causing systemic infection. Daily therapeutic dosing (5 mg/kg of body weight) of caspofungin resulted in no reduction in fecal burdens, organ breakthrough rates similar to control groups, and resistance rates (0 to 10%) similar to those reported clinically. Treatment with 20 mg/kg caspofungin initially reduced burdens, but a rebound following 5 to 9 days of treatment was accompanied by high levels of resistance (FKS1/FKS2 mutants). Although breakthrough rates decreased in this group, the same FKS mutants were recovered from organs. In an attempt to negate drug tolerance that is critical for resistance development, we cotreated mice with daily caspofungin and the chitin synthase inhibitor nikkomycin Z. The largest reduction (3 log) in GI burdens was obtained within 3 to 5 days of 20 mg/kg caspofungin plus nikkomycin treatment. Yet, echinocandin resistance, characterized by a novel Fks1-L630R substitution, was identified following 5 to 7 days of treatment. Therapeutic caspofungin plus nikkomycin treatment left GI burdens unchanged but significantly reduced organ breakthrough rates (20%; P < 0.05). Single-dose pharmacokinetics demonstrated low levels of drug penetration into the GI lumen posttreatment with caspofungin. Overall, we show that C. glabrata echinocandin resistance can arise within the GI tract and that resistant mutants can readily disseminate upon immunosuppression.


[Young adult with psychotic disorders have problems relating to sexuality, intimacy and relationships. An explanatory study based on focus group].
Research has shown that young adults with psychotic disorders frequently have problems relating to sexuality, intimacy and relationships. Such problems are often neglected in clinical practice. To perform a study that explores, on the basis of focus groups, how issues such as sexuality, intimacy and relationships can be addressed as part of the treatment of adolescents suffering from a psychotic disorder. We created eight focus groups consisting of clients attending the department of psychotic disorders and caregivers who worked there. The meetings of each focus group were fully transcribed and analysed by means of Nvivo. Clients indicated they wanted to address the topics of sexuality, intimacy and relationships in a group setting. They expressed the wish to have mixed gender groups and decided that in the group discussions the main focus should be on the exchange of personal experiences. In our view, it is desirable that psychiatry should pay more attention to the subject of sexuality. By giving adolescents suffering from psychotic disorders the opportunity to discuss their experiences, problems and feelings of insecurity in a group setting and in a low-threshold environment, psychiatrists can greatly improve the quality of care that they provide for their patients.


Long-term effects of cardiac resynchronisation therapy in patients with atrial fibrillation.
To compare the effects of cardiac resynchronisation therapy (CRT) in patients with heart failure (HF) in either atrial fibrillation (AF) or sinus rhythm (SR). Prospective observational study. 295 consecutive patients with HF (permanent AF in 66, paroxysmal AF in 20, SR in 209; New York Heart Association (NYHA) class III or IV; left ventricular ejection fraction (LVEF) <or=35%, QRS >or=120 ms). All patients underwent CRT without atrioventricular junction ablation. The primary end point was the composite of cardiovascular death or unplanned hospitalisation for major cardiovascular events. Secondary end points included the composite of cardiovascular death or hospitalisation for worsening HF. Cardiovascular mortality, total mortality and changes in NYHA class, 6-minute walking distance, quality of life (Minnesota Living with Heart Failure questionnaire) and echocardiographic variables were also considered. Over a follow-up period of up to 6.8 years, no differences emerged between patients in AF or SR in any of the mortality or morbidity end points. The AF and SR groups derived similar improvements in mean NYHA class (-1.3 vs -1.2), 6-minute walking distance (92.3 vs 78.4 m) and quality of life scores (-25.2 vs -18.7) (all p<0.001). In both the AF and the SR groups, reductions were seen in left ventricular end-systolic (-25.9 vs -34.5 ml, both p<0.001) and end-diastolic (-20.2 ml, p = 0.001 vs 26.2 ml, p<0.001) volumes and improvements in LVEF (4.69% vs 7.86%, both p<0.001). Cardiac resynchronisation therapy leads to similar prognostic and symptomatic benefits in patients in AF and SR, even without atrioventricular junction ablation. Echocardiographic improvements are also comparable.


Stearic acid accumulation in macrophages induces toll-like receptor 4/2-independent inflammation leading to endoplasmic reticulum stress-mediated apoptosis.
Elevated serum free fatty acid levels are associated with an increased risk of cardiovascular disease and type 2 diabetes mellitus. Macrophages are recruited to atherosclerotic plaques and metabolic tissues during obesity and accumulate lipids, including free fatty acids. We investigated the molecular consequences of intracellular saturated free fatty acid accumulation in macrophages. Previously, we demonstrated that cotreatment of mouse peritoneal macrophages (MPMs) with stearic acid and triacsin C (an inhibitor of long-chain acyl coenzyme A synthetases) results in intracellular free fatty acid accumulation and apoptosis. Here, we used Western blotting analysis, real-time reverse transcription polymerase chain reaction, and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining to assess endoplasmic reticulum (ER) stress, inflammation, and apoptosis in MPMs. Intracellular stearic acid accumulation induces Toll-like receptor 4/2-independent inflammation that results in ER stress-mediated apoptosis of MPMs. Polarization of MPMs to a proinflammatory M1 phenotype increases their susceptibility to inflammation and ER stress, but not apoptosis, in response to cotreatment with stearic acid and triacsin C. Intracellular accumulation of stearic acid in MPMs activates inflammatory signaling, leading to ER stress-mediated apoptosis. M1 macrophages are more prone to stearic acid-induced inflammation and ER stress. These same pathways may be activated in macrophages residing in atherosclerotic plaques and metabolic tissues during conditions of obesity and hyperlipidemia.


Echocardiographic evaluation of size, function, and mass of normal and hypertrophied rat ventricles.
The noninvasive evaluation of cardiac structure and function in small animals would provide a means for investigators to repeatedly evaluate treatment effects at various stages of experimental protocols. In this study, commercially available echocardiographic and Doppler equipment was utilized to evaluate hypertrophied (HYP) and normal (SH) rat hearts. Surgically induced renovascular hypertension was used to produce a 35% increase in left ventricular (LV) weight in HYP relative to SH hearts. A commercially available echocardiographic system with integral Doppler capabilities and a 7.5-mHz single-crystal mechanical transducer was used to obtain parasternal long- and short-axis images of HYP and SH hearts in anesthetized animals. HYP hearts were found to have normal systolic function, as evidenced by preserved LV systolic and diastolic dimensions and volumes as well as fractional shortening and ejection fraction. HYP hearts demonstrated a 62% increase in their echocardiographically measured LV posterior wall thicknesses and a 44% increase in calculated ventricular mass. Both parameters were reliable in predicting the presence and degree of left ventricular hypertrophy. Doppler flow velocities through the aortic root and pulmonic valve did not differ between groups, again suggesting preserved LV systolic performance. These results indicate that two-dimensional echocardiography provides a useful means to noninvasively evaluate cardiac structure and function in rats.


Effect of class F fly ash on fine sand compaction through soil stabilization.
This paper presents the results of an experimental investigation carried out to evaluate the effect of fly ash (FA) on fine sand compaction and its suitability as a material for embankments. The literature review demonstrates the lack of research on stabilization of sandy material using FA. The study is concerned with the role of FA content in stabilized soil physical characteristics. The main aim of this paper is to determine the optimum quantity of FA content for stabilization of this type of soil. This is achieved through particle size distribution and compaction (standard proctor) tests. The sand was stabilized with three proportions of FA (5%, 10% and 15%) and constant cement content of 3% was used as an activator. For better comparison, the sand was also stabilized by 3% cement only so that the effect of FA could be observed more clearly. The results were in line with the literature for other types of soil, i.e. as the % of FA increases, reduction in maximum dry density and higher optimum moisture content were observed.


Novel clinically meaningful scores for the ICIQ-UI-SF and ICIQ-FLUTS questionnaires in women with stress incontinence.
To establish, for the first time, the clinically important differences for the ICIQ-UI-SF and ICIQ-FLUTS questionnaires following surgical and conservative treatments for stress-predominant urinary incontinence in women. Data from the SIMS and OPAL randomised controlled trials were analysed using an anchor-based method. Clinically important difference (CID; score change indicating a successful outcome) and minimal important difference (MID; score change indicating the smallest noticeable difference) were estimated using the PGI-I scale as the anchor. For ICIQ-UI-SF, following surgical management, CIDs were 5.0 (95%CI 4.3, 5.6) at 1 year and 4.9 points (95%CI 4.2, 5.5) at 3 years, while following conservative management, CIDs were 4.0 (95%CI 3.4, 4.5) at 1 year and 4.6 points (95%CI 4.0, 5.2) at 2 years. For ICIQ-FLUTS, the CID was 3.4 points (95%CI 2.9, 4.0) at 1 year for both surgical and conservative management. MIDs for ICIQ-UI-SF, after surgical treatment, were 4.7 (95% CI 3.2, 6.1) at 1 year and 1.6 points (95%CI -0.2, 3.0) at 3 years, and after conservative treatment they were 1.7 (95% CI 1.0, 2.5) at 1 year and 1.9 points (95%CI 1.1, 2.7) at 2 years. For ICIQ-FLUTS, MIDs were 1.8 (95% CI 0.6, 3.1) at 1 year and 3.2 points (95%CI 2.0, 4.4) at 2 years after surgical treatment, and 1.3 (95%CI 0.6, 1.9) at 1 year and 1.9 points (95%CI 1.1, 2.6) at 2 years after conservative treatment. Our study is the first to establish the CID for the ICIQ-UI-SF and ICIQ-FLUTS that women would associate with a successful outcome 3-years post-surgery and 2-years post-conservative treatment of stress-predominant urinary incontinence. The MID was lower following conservative compared to surgical treatment.


Sorafenib and vorinostat kill colon cancer cells by CD95-dependent and -independent mechanisms.
We examined the interaction between the multikinase inhibitor sorafenib and histone deacetylase inhibitors. Sorafenib and vorinostat synergized (sorafenib + vorinostat) to kill HCT116 and SW480 cells. In SW480 cells, sorafenib + vorinostat increased CD95 plasma membrane levels and promoted death-inducing signal complex (DISC) formation, and drug toxicity was blocked by knockdown of CD95 or overexpression of cellular FLICE-like inhibitory protein (c-FLIP-s). In SW620 cells that are patient-matched to SW480 cells, sorafenib + vorinostat toxicity was significantly lower, which correlated with a lack of CD95 activation and lower expression of ceramide synthase 6 (LASS6). Overexpression of LASS6 in SW620 cells enhanced drug-induced CD95 activation and enhanced tumor cell killing, whereas knockdown of LASS6 in SW480 cells suppressed CD95 activation. Knocking down LASS6 expression also suppressed CD95 activation in hepatoma, pancreatic, and ovarian cancer cells. In HCT116 cells, sorafenib + vorinostat treatment caused DISC formation without reducing c-FLIP-s expression and did not increase CD95 plasma membrane levels; sorafenib + vorinostat exposure killed HCT116 cells via an intrinsic pathway/caspase 9-dependent mechanism. In HCT116 cells, knockdown of CD95 enhanced sorafenib + vorinostat lethality, which correlated with less drug-induced CD95-dependent autophagy. Sorafenib + vorinostat treatment activated the c-Jun NH(2)-terminal kinase pathway, which was causal in promoting dissociation of Beclin1 from BCL-2, and in promoting autophagy. Knockdown of Beclin1 expression blocked autophagy and enhanced drug toxicity. Our data demonstrate that treatment of colon cancer cells with sorafenib + vorinostat activates CD95 via de novo ceramide synthesis that promotes viability via autophagy or degrades survival via either the extrinsic or intrinsic pathways.


Induction of DNA ligase I by 1-beta-D-arabinosylcytosine and aphidicolin in MiaPaCa human pancreatic cancer cells.
Exposure of MiaPaCa cells to 1-beta-D-arabinosylcytosine (ara-C) resulted in an increase in DNA ligase levels up to threefold compared to that in the untreated control cells, despite significant growth inhibition. Increased levels of DNA ligase I protein appear to correlate with the appearance of increased mRNA levels. The [(3)H]thymidine incorporation experiment and the biochemical assay of total polymerase activity revealed that an increase in DNA ligase I levels after treatment with ara-C was not accompanied by an increase of DNA synthesis or an increased presence of DNA polymerase activity inside cells. When cells resumed DNA synthesis after drug treatment, DNA ligase I levels began to drop, indicating that increased DNA ligase I is not required for DNA synthesis. An increase in DNA ligase I was also observed in cells treated with aphidicolin, another inhibitor of DNA synthesis that inhibits DNA polymerases without incorporating itself into DNA, indicating that an increase in DNA ligase I levels could be caused by the arrest of DNA replication by these agents. Interestingly, caffeine, which is a well-known inhibitor of DNA damage checkpoint kinases, abrogated the increase in DNA ligase I in MiaPaCa cells treated with ara-C and aphidicolin, suggesting that caffeine-sensitive kinases might be important mediators in the pathway leading to the increase in DNA ligase I levels in response to anticancer drugs, including ara-C and aphidicolin. We propose that ara-C and aphidicolin induce damage to the DNA strand by arresting DNA replication forks and subsequently increase DNA ligase I levels to facilitate repair of DNA damage.


Crowned Dens syndrome.
Patients with crowned dens syndrome typically present with severe neck pain and have calcium deposits around the odontoid process of the axis on radiographs. To our knowledge, the cases of only thirty-five patients have been reported in the English-language literature and the clinical features remain unclear. The purposes of this study were to examine the clinical features of crowned dens syndrome, determine treatment outcomes, and propose diagnostic criteria. Forty patients with severe neck pain had calcium deposition around the odontoid process on computed tomography scans, and they were thus diagnosed as having crowned dens syndrome. Data were collected in relation to these patients, including the date of onset of neck pain, the presence of inflammatory indicators (increased body temperature, C-reactive protein levels, and white blood-cell count), and treatment outcomes. The male-to-female ratio was 0.6, and two-thirds of the patients were more than seventy years of age. All patients had markedly restricted neck motion, particularly in rotation, and all had one or more positive inflammatory indicators. Calcium deposition was detected in all areas around the odontoid process, but chiefly behind the process. Pain was typically relieved by nonsteroidal anti-inflammatory drugs, prednisolone, or both. A combination of both appeared to be the most effective. We believe that crowned dens syndrome is more common than previously recognized, especially in elderly patients. It is diagnosed on the basis of acute and severe neck pain; marked restriction of neck motion, particularly in rotation; the presence of inflammatory indicators, such as an elevated C-reactive protein level; calcium deposition around the odontoid process detected by computed tomography; no history of trauma; and the exclusion of other inflammatory diseases and tumors. Prednisolone and nonsteroidal anti-inflammatory drugs in combination are the recommended treatment for symptom relief.


Enhanced recognition of disgust in bipolar illness.
Bipolar disorder is associated with functional and structural abnormalities in the brain circuits involved in processing emotional stimuli. Although impairments of cognitive function have been found to persist in bipolar patients during periods of euthymic mood, it is not known whether abnormalities in emotional processing also occur during these periods of recovery. The present investigation assessed the ability of euthymic patients with bipolar disorder to recognize different facial expressions of emotion, compared with matched controls. A nonemotional facial categorization task was used to control for possible nonspecific differences in perception or attention. In contrast to the small impairments seen in the nonemotional categorization task, patients with bipolar disorder showed a robust facilitation in the discrimination of disgusted facial expressions. The recognition of other basic negative and positive emotions was unchanged. The present results suggest a selective facilitation of the processes involved in recognizing facial expressions of disgust in patients with bipolar disorder. This difference in perception may be relevant to the decreased self-esteem and social functioning that have been associated with the euthymic phase of this disorder.


Adenosine, Lidocaine, and Magnesium Support a High Flow, Hypotensive, Vasodilatory State With Improved Oxygen Delivery and Cerebral Protection in a Pig Model of Noncompressible Hemorrhage.
Noncompressible hemorrhage is the leading cause of preventable death in military and civilian trauma. Our aim was to examine the effect of adenosine, lidocaine, and magnesium (Mg2+; ALM) on cardiovascular and cerebral function in a porcine hepatic hemorrhage model. Pigs (59.1 ± 0.34 kg) were anesthetized, instrumented, and randomly assigned into sham (n = 6), saline controls (n = 10) or ALM (n = 10) groups before laparoscopic liver resection. After 30 min, groups received 4 mL/kg 3% NaCl ± ALM bolus (Phase 1) followed 60 min later with 3 mL/kg/h 0.9% NaCl ± ALM drip (4 h; Phase 2), then transfusion. Hemodynamics, carotid artery flow, and intracranial pressure were measured continuously. Microdialysis samples were analyzed for metabolites. Saline controls had 20% mortality (mean survival time: 307 ± 38 min) with no ALM deaths over 6 h. Bolus administration increased mean arterial pressure (MAP) in both groups, and drip led to further increases to 62 ± 10 mmHg in controls compared with a steady fall to 47 ± 8 mmHg in ALM group at 240 min. The lower MAP was associated with a dramatic fall in systemic vascular resistance and improved oxygen delivery. ALM drip significantly increased cardiac output and stroke volume with lower dP/dtMin, indicating a less stiff heart. ALM drip also significantly decreased cerebral perfusion pressure, reduced cerebral oxygen consumption (28%), and reduced brain glycerol (60%), lactate (47%), and relative expression of hypoxia-inducible factor (38%) compared with saline controls. ALM therapy improved cardiac function and oxygen delivery by lowering systemic vascular resistance after noncompressible hemorrhage. ALM also appeared to protect the brain at hypotensive MAPs with significantly lower cerebral perfusion pressure, lower O2 consumption, and significantly lower cortical lactate and glycerol levels compared to saline controls.


Candida esophagitis: species distribution and risk factors for infection.
Although Candida albicans is the main cause of fungal esophagitis, other species such as C. tropicalis, C. krusei and C. stellatoidea have also been implicated. Several studies have identified risk factors for C. albicans esophagitis. However, data for non-C. albicans species is still sparse. The aim of this study was to determine the etiology of Candida esophagitis in our medical centre over an 18-month period. Additionally, we aimed to investigate predisposing conditions for esophageal candidosis caused by different Candida species. A total of 21,248 upper gastroscopies were performed in Santa Casa Complexo Hospitalar between January 2005 and July 2006. The prevalence of Candida esophagitis was 0.74% (n = 158). C. albicans caused the vast majority of infections (96.2%), followed by C. tropicalis (2.5%), C. lusitaniae (0.6%) and C. glabrata (0.6%). There were 81 women (51.3%) and 77 men (48.7%). No case of mixed infection occurred. Concomitant oral candidosis was documented for 10.8% (n = 17). Most of cases (55.1%) involved outpatients. Around one fifth of patients in our cohort had no identifiable risk factors for esophageal candidosis (20.8%). Since nearly all infections were caused by C. albicans we were not able to determine risk factors for esophagitis caused by other Candida species.


The effect of mutations in alpha-tropomyosin (E40K and E54K) that cause familial dilated cardiomyopathy on the regulatory mechanism of cardiac muscle thin filaments.
E40K and E54K mutations in alpha-tropomyosin cause inherited dilated cardiomyopathy. Previously we showed, using Ala-Ser alpha-tropomyosin (AS-alpha-Tm) expressed in Escherichia coli, that both mutations decrease Ca(2+) sensitivity. E40K also reduces V(max) of actin-Tm-activated S-1 ATPase by 18%. We investigated cooperative allosteric regulation by native Tm, AS-alpha-Tm, and the two dilated cardiomyopathy-causing mutants. AS-alpha-Tm has a lower cooperative unit size (6.5) than native alpha-tropomyosin (10.0). The E40K mutation reduced the size of the cooperative unit to 3.7, whereas E54K increased it to 8.0. For the equilibrium between On and Off states, the K(T) value was the same for all actin-Tm species; however, the K(T) value of actin-Tm-troponin at pCa 5 was 50% less for AS-alpha-Tm E40K than for AS-alpha-Tm and AS-alpha-Tm E54K. K(b), the "closed" to "blocked" equilibrium constant, was the same for all tropomyosin species. The E40K mutation reduced the affinity of tropomyosin for actin by 1.74-fold, but only when in the On state (in the presence of S-1). In contrast the E54K mutation reduced affinity by 3.5-fold only in the Off state. Differential scanning calorimetry measurements of AS-alpha-Tm showed that domain 3, assigned to the N terminus of tropomyosin, was strongly destabilized by both mutations. Additionally with AS-alpha-Tm E54K, we observed a unique new domain at 55 degrees C accounting for 25% of enthalpy indicating stabilization of part of the tropomyosin. The disease-causing mechanism of the E40K mutation may be accounted for by destabilization of the On state of the thin filaments; however, the E54K mutation has a more complex effect on tropomyosin structure and function.


Determinants of reproductive health and related quality of life among Indian women in mining communities.
This article is a report of a mixed method to examine the determinants of reproductive health and quality of life among Indian women. Reproductive health among married women in stressed regions of industrialized countries is an increasingly important consideration, but little is known about the important factors influencing reproductive health and quality of life. A descriptive correlational research design was used between January and April 2006 with 145 randomly selected married women in a rural mining region of India. The instruments used were the Reproductive Health Index Questionnaire and Interview and Ferrans and Power's Quality of Life Index. Inferential statistics were done using anova and manova. Thematic content analysis was used to analyse qualitative data. Reproductive health and quality of life was low among Indian women in mining communities. Higher age groups, better economic status, higher age at menarche, fewer number of children, absence of long-term illness, reproductive illness and domestic violence were important determinants of reproductive health and quality of life among these women in mining communities. The findings suggest that physical, psychological, sexual, family, socio-economic, energy level and cognitive domains of reproductive health and quality of life need to be assessed and are influenced by important determinants among women. These domains reflected in the theory of goal attainment should be an essential part of nursing process for providing women's reproductive health care in the mining community.


Effect of the first federally funded US antismoking national media campaign.
Every year, smoking kills more than 5 million people globally, including 440,000 people in the USA, where the long-term decline in smoking prevalence has slowed. The US Centers for Disease Control and Prevention (CDC) delivered a national, 3-month antismoking campaign called Tips From Former Smokers (Tips) that started in March, 2012, in which hard-hitting, emotionally evocative television advertising was featured, depicting smoking-related suffering in real people. We aimed to assess the effects of the Tips campaign. We undertook baseline and follow-up surveys of nationally representative cohorts of adult smokers and non-smokers. The national effect of the Tips campaign was estimated by applying rates of change in the cohort before and after the campaign to US census data. 3051 smokers and 2220 non-smokers completed baseline and follow-up assessments. 2395 (78%) smokers and 1632 (74%) non-smokers recalled seeing at least one Tips advertisement on television during the 3-month campaign. Quit attempts among smokers rose from 31.1% (95% CI 30.3-31.9) at baseline to 34.8% (34.0-35.7) at follow-up, a 12% relative increase. The prevalence of abstinence at follow-up among smokers who made a quit attempt was 13.4% (95% CI 9.7-17.2). Nationally, an estimated 1.64 million additional smokers made a quit attempt, and 220,000 (95% CI 159,000-282,000) remained abstinent at follow-up. Recommendations by non-smokers to quit grew from 2.6% at baseline to 5.1% at follow-up, and the prevalence of people talking with friends and family about the dangers of smoking rose from 31.9% (95% CI 31.3-32.5) to 35.2% (34.6-35.9), resulting in an estimated 4.7 million additional non-smokers recommending cessation services and more than 6 million talking about the dangers of smoking. The high-exposure Tips media campaign was effective at increasing population-level quit attempts. The growth in smokers who quit and became sustained quitters could have added from a third to almost half a million quality-adjusted life-years to the US population. Expanded implementation of similar campaigns globally could accelerate progress on the WHO Framework Convention on Tobacco Control and reduce smoking prevalence globally. CDC, US Department of Health and Human Services.


The quantitative relationship between structure and polarized spectroscopy in the FMO complex of Prosthecochloris aestuarii: refining experiments and simulations.
New absorption, linear dichroism (LD) and circular dichroism (CD) measurements at low temperatures on the Fenna-Matthews-Olson complex from Prosthecochloris aestuarii are presented. Furthermore, the anisotropy of fluorescence excitation spectra is measured and used to determine absolute LD spectra, i.e. corrected for the degree of orientation of the sample. In contrast to previous studies, this allows comparison of not only the shape but also the amplitude of the measured spectra with that calculated by means of an exciton model. In the exciton model, the point-dipole approximation is used and the calculations are based on the trimeric structure of the complex. An improved description of the absorption and LD spectra by means of the exciton model is obtained by simply using the same site energies and coupling strengths that were given by Louwe et al. (1997, J Phys Chem B 101: 11280-11287) and including three broadening mechanisms, which proved to be essential: Inhomogeneous broadening in a Monte Carlo approach, homogeneous broadening by using the homogeneous line shape determined by fluorescence line-narrowing measurements [Wendling et al. (2000) J Phys Chem B 104: 5825-5831] and lifetime broadening. An even better description is obtained when the parameters are optimized by a global fit of the absorption, LD and CD spectra. New site energies and coupling strengths are estimated. The amplitude of the LD spectrum is described quite well. The shape of the CD spectrum is modelled in a satisfactory way but its size can only be simulated by using a rather large value for the index of refraction of the medium surrounding the chromophores. It is shown that the estimated coupling strengths are compatible with the value of the dipole strength of bacteriochlorophyll a, when using the empty-cavity model for the local-field correction factor.


Effects of rapid tryptophan depletion in patients with seasonal affective disorder in remission after light therapy.
Previous studies show that rapid tryptophan depletion reverses the effects of therapy with serotonergic, but not noradrenergic, antidepressant drugs in patients with remitted nonseasonal depression. The objective of this study was to investigate the effects of rapid tryptophan depletion in patients with seasonal affective disorder (SAD) that was in clinical remission after light therapy. Patients who met DSM-III-R criteria for recurrent major depressive episodes, seasonal (winter) pattern (equivalent to SAD), were treated with a standard course of light therapy. Ten patients with SAD in clinical remission after light therapy underwent rapid tryptophan depletion in a placebo-controlled, double-blind crossover study. Behavioral ratings and plasma tryptophan levels were obtained before and after rapid tryptophan depletion. Plasma total and free tryptophan levels were significantly reduced to 20% of normal levels by the rapid tryptophan depletion. The depletion session resulted in significant increases in depression scores compared with the sham control session. Six of 10 patients had a clinically significant relapse of their depression following the tryptophan depletion session. Rapid tryptophan depletion appears to reverse the antidepressant effect of bright light therapy in patients with SAD. This suggests that the therapeutic effects of bright light in SAD may involve a serotonergic mechanism.


Integrating Physical Activity in Primary Care Practice.
Based on a collaborative symposium in 2014 hosted by the Society of Behavioral Medicine (SBM) and the American College of Sports Medicine (ACSM), this paper presents a model for physical activity counseling for primary care physicians (PCPs). Most US adults do not meet national recommendations for physical activity levels. Socioecological factors drive differences in physical activity levels by geography, sex, age, and racial/ethnic group. The recent Patient Protection and Affordable Care Act incentivizes PCPs to offer patients physical activity counseling. However, PCPs have reported socioecological barriers to physical activity counseling and also patient barriers to physical activity, spanning from the individual to the environmental (eg, lack of safe spaces for physical activity), policy (eg, reimbursement policies), and organizational (eg, electronic medical record protocols, worksite norms/policies) levels. The aims of this paper are to: 1) discuss barriers to PCP counseling for physical activity; 2) provide evidence-based strategies and techniques to help PCPs address these counseling barriers; and 3) suggest practical steps for PCPs to counsel patients on physical activity using strategies and supports from policy, the primary care team, and other support networks.


A key interaction with RPA orients XPA in NER complexes.
The XPA protein functions together with the single-stranded DNA (ssDNA) binding protein RPA as the central scaffold to ensure proper positioning of repair factors in multi-protein nucleotide excision repair (NER) machinery. We previously determined the structure of a short motif in the disordered XPA N-terminus bound to the RPA32C domain. However, a second contact between the XPA DNA-binding domain (XPA DBD) and the RPA70AB tandem ssDNA-binding domains, which is likely to influence the orientation of XPA and RPA on the damaged DNA substrate, remains poorly characterized. NMR was used to map the binding interfaces of XPA DBD and RPA70AB. Combining NMR and X-ray scattering data with comprehensive docking and refinement revealed how XPA DBD and RPA70AB orient on model NER DNA substrates. The structural model enabled design of XPA mutations that inhibit the interaction with RPA70AB. These mutations decreased activity in cell-based NER assays, demonstrating the functional importance of XPA DBD-RPA70AB interaction. Our results inform ongoing controversy about where XPA is bound within the NER bubble, provide structural insights into the molecular basis for malfunction of disease-associated XPA missense mutations, and contribute to understanding of the structure and mechanical action of the NER machinery.


Bifurcation analysis of an existing mathematical model reveals novel treatment strategies and suggests potential cure for type 1 diabetes.
Type 1 diabetes is a disease with serious personal and socioeconomic consequences that has attracted the attention of modellers recently. But as models of this disease tend to be complicated, there has been only limited mathematical analysis to date. Here we address this problem by providing a bifurcation analysis of a previously published mathematical model for the early stages of type 1 diabetes in diabetes-prone NOD mice, which is based on the data available in the literature. We also show positivity and the existence of a family of attracting trapping regions in the positive 5D cone, converging towards a smaller trapping region, which is the intersection over the family. All these trapping regions are compact sets, and thus, practical weak persistence is guaranteed. We conclude our analysis by proposing 4 novel treatment strategies: increasing the phagocytic ability of resting macrophages or activated macrophages, increasing the phagocytic ability of resting and activated macrophages simultaneously and lastly, adding additional macrophages to the site of inflammation. The latter seems counter-intuitive at first glance, but nevertheless it appears to be the most promising, as evidenced by recent results.


Prolonged oxidative stress impairs insulin-induced GLUT4 translocation in 3T3-L1 adipocytes.
Prolonged exposure of 3T3-L1 adipocytes to micromolar concentrations of H2O2 results in an impaired response to the acute metabolic effects of insulin. In this study, we further characterized the mechanisms by which oxidative stress impairs insulin stimulation of glucose transport activity. Although insulin induced a 2.5-fold increase in plasma membrane GLUT4 content and a 50% reduction in its abundance in the low-density microsomal (LDM) fraction in control cells, oxidation completely prevented these responses. The net effect of insulin on 2-deoxyglucose uptake activity was reduced in oxidized cells and could be attributed to GLUT1 translocation. Insulin stimulation of insulin receptor substrate (IRS) 1 tyrosine phosphorylation and the association of IRS-1 with phosphatidylinositol (PI) 3-kinase were not impaired by oxidative stress. However, a 1.9-fold increase in the LDM content of the p85 subunit of PI 3-kinase after insulin stimulation was observed in control, but not in oxidized, cells. Moreover, although insulin induced an increase in IRS-1-associated PI 3-kinase activity in the LDM in control cells, this effect was prevented by oxidation. These findings suggest that prolonged low-grade oxidative stress impairs insulin-stimulated GLUT4 translocation, potentially by interfering with compartment-specific activation of PI 3-kinase.


Analysis of electrical brain waves in neurotoxicology: γ-hydroxybutyrate.
Advances in computer technology have allowed quantification of the electroencephalogram (EEG) and expansion of quantitative EEG (qEEG) analysis in neurophysiology, as well as clinical neurology, with great success. Among the variety of techniques in this field, frequency (spectral) analysis using Fast Fourier Transforms (FFT) provides a sensitive tool for time-course studies of different compounds acting on particular neurotransmitter systems. Studies presented here include Electrocorticogram (ECoG) analysis following exposure to a glutamic acid analogue - domoic acid (DOM), psychoactive indole alkaloid - ibogaine, as well as cocaine and gamma-hydroxybutyrate (GHB). The ECoG was recorded in conscious rats via a tether and swivel system. The EEG signal frequency analysis revealed an association between slow-wave EEG activity delta and theta and the type of behavioral seizures following DOM administration. Analyses of power spectra obtained in rats exposed to cocaine alone or after pretreatment with ibogaine indicated the contribution of the serotonergic system in ibogaine mediated response to cocaine (increased power in alpha(1) band). Ibogaine also lowered the threshold for cocaine-induced electrographic seizures (increased power in the low-frequency bands, delta and theta). Daily intraperitoneal administration of cocaine for two weeks was associated with a reduction in slow-wave ECoG activity 24 hrs following the last injection when compared with controls. Similar decreased cortical activity in low-frequency bands observed in chronic cocaine users has been associated with reduced metabolic activity in the frontal cortex. The FFT analyses of power spectra relative to baseline indicated a significant energy increase over all except beta(2) frequency bands following exposure to 400 and 800 mg/kg GHB. The EEG alterations detected in rats following exposure to GHB resemble absence seizures observed in human petit mal epilepsy. Spectral analysis of the EEG signals combined with behavioral observations may prove to be a useful approach in studying chronic exposure to drugs of abuse and treatment of drug dependence.


Acoustic nonlinearity parameters for transversely isotropic polycrystalline materials.
This article considers polycrystalline materials with macroscopic elastic anisotropy and the effect of the anisotropy on the quadratic nonlinearity parameter used to describe second harmonic generation in solids. The polycrystal is assumed to have transversely isotropic elastic symmetry, which leads to a directional dependence of the nonlinearity parameters. Additionally, the anisotropy leads to second harmonic generation from an input shear wave. Estimates of the longitudinal and shear wave nonlinearity parameters are given as a function of single-crystal elastic constants, macroscopic anisotropy constants, and propagation direction. An inverse model is presented that relates measured nonlinearity parameters to the macroscopic anisotropy constants. The estimates of the nonlinearity parameters can be used to approximate the damage-free or baseline nonlinearity parameter of structural components, which helps the effort toward absolute measures of material damage.