Occupational Risk in Knee Osteoarthritis: A Systematic Review and Meta-Analysis of Observational Studies.
To assess the association between occupational exposures and knee osteoarthritis (OA). We systematically searched for observational studies that examined the relationship between occupational exposures and knee OA and total knee replacement. Four databases were searched up to October 1, 2019. Two reviewers independently assessed study quality using the Newcastle-Ottawa Scale and evidence quality using the Grading of Recommendations Assessment, Development and Evaluation approach. Subgroup meta-analyses were conducted for important study characteristics and each type of occupational exposure. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated for the meta-analysis using random-effects models. Eighty eligible studies were identified including 25 case-control (n = 20,505 total participants), 36 cross-sectional (n = 139,463 total participants), and 19 cohort studies (n = 16,824,492 total participants). A synthesis of 71 studies suggested increased odds of knee OA (OR 1.52 [95% CI 1.37-1.69]) by combining different physically demanding jobs and occupational activities as compared to sedentary occupations and/or low-exposure groups. Odds of knee OA were greater in males and in industry-based studies and studies assessing lifetime occupational exposures. There were 9 specific job titles that were associated with knee OA, including farmer, builder, metal worker, and floor layer. Occupational lifting, kneeling, climbing, squatting, and standing were all associated with higher odds of knee OA as compared to the odds of knee OA in sedentary workers. Strenuous, physically demanding occupations and occupational activities were associated with increased odds of knee OA as supported by moderate-quality evidence. Specifically, agricultural and construction sectors, which typically involve heavy lifting, frequent climbing, prolonged kneeling, squatting, and standing, carried increased odds of knee OA.


Saliva secretion and efficacy of helicobacter pylori eradication in peptic ulcer patients.
It has been noted that the presence of Helicobacter pylori (H. pylori) in the oral cavity may affect the outcome of eradication therapy. This condition is associated with the recurrence of gastric infection. The optimum secretion of saliva promotes oral health consequently influencing H. pylori eradication. The purpose of this study was to investigate the relation between salivary secretion and the efficacy of H. pylori eradication from the stomach. Forty five patients with gastric H. pylori infection were enrolled in this study. Diagnosis of H. pylori infection was confirmed by endoscopy, biopsy, urease test and histological examination. Salivary secretion of all participants was determined under standard condition before the beginning of antibacterial treatment. Then the patients were treated with a 14-day course anti-H. pylori regimen consisting of amoxicillin, omeprazole, metronidazole and bismuth. The efficacy of eradication therapy was evaluated 4 weeks after the end of the treatment course. Mann-Whitney U test was used to analyze the variables. The median of salivary secretion among successful and unsuccessful H. pylori eradication groups was 0.48 ml/min and 0.24 ml/min, respectively (p=0.005). Although the type of drug regimens is challenging, the efficacy of H. pylori eradication from the stomach might be reduced by lower salivary secretion.


HIV Risk among trafficked women: a systematic review of the global literature.
This review examines the global literature concerning HIV/STI risk among trafficked female sex workers (FSWs), in relation to sex trafficking and drug use. The compound effects of sexual and drug-related risk merit a systematic literature review to grant a better understanding of their role in HIV/STI transmission. The current review synthesizes the results of 21 studies conducted in multiple cultural settings. Though the selected studies similarly found heightened HIV risks faced by trafficked FSWs, the focuses varied from the effect of trafficking on HIV, to the effect of entry age to sex work on HIV, to the effects of various forms of violence on HIV, to the effect of HIV risk behaviors on HIV, and to the relationship between HIV and other STIs. While focuses and findings varied, they are in consensus that various forms of violence and diminished autonomy, as a result of sex trafficking, accelerate the FSWs' risks of HIV/STIs even in comparison to women who voluntarily enter the sex trade. Variations in findings may be attributed to specific socio-cultural settings and various research methods as well as differences in the risk factors being studied. This points to the need for more empirical studies - particularly those that specifically target trafficked FSWs and the mechanisms of HIV/STI transmissions among the highly vulnerable population..


Effect of viral upper respiratory tract infection on cough reflex sensitivity.
Acute viral upper respiratory tract infection (URI; common cold) is among the most common medical conditions affecting man, with cough being a typical feature of the associated syndrome. Studies employing capsaicin inhalation challenge to measure cough reflex sensitivity have demonstrated a transient tussive hyperresponsiveness induced by URI that reverts to normal by 4-8 weeks post infection. Mechanisms proposed to explain the induction of cough by URI include a number of infection-associated airway effects, such as enhanced release of cytokines, neurotransmitters, and leukotrienes; increased neural receptor levels; reduced activity of neutral endopeptidases; transient modulation of afferent neural activity; mucus hypersecretion; and, possibly, effects on cholinergic motor pathways. Recent studies evaluating urge-to-cough (UTC), the sensation of irritation preceding the motor act of coughing, have demonstrated that URI induces a transient enhancement of UTC analogous to the effect observed on cough reflex sensitivity. The recently introduced concept of the Cough Hypersensitivity Syndrome may provide an explanation for the commonly observed clinical phenomenon of acute viral URI triggering what will develop into chronic, refractory cough in a subgroup of patients.


Serum albumin disrupts Cryptococcus neoformans and Bacillus anthracis extracellular vesicles.
For both pathogenic fungi and bacteria, extracellular vesicles have been shown to contain many microbial components associated with virulence, suggesting a role in pathogenesis. However, there are many unresolved issues regarding vesicle synthesis and stability, including the fact that vesicular packaging for extracellular factors involved in virulence must also have a mechanism for vesicle unloading. Consequently, we studied the kinetics of vesicle production and stability using [1-(14) C] palmitic acid metabolic labelling and dynamic light scattering techniques. Cryptococcus neoformans vesicles were produced throughout all stages of fungal culture growth and they were stable once isolated. Density gradient analysis revealed that only a portion of the vesicle population carried cryptococcal polysaccharide, implying heterogeneity in vesicular cargo. Vesicle incubation with macrophages resulted in rapid vesicle instability, a phenomenon that was ultimately associated with serum albumin. Additionally, albumin, along with mouse serum and murine immunoglobulin destabilized Bacillus anthracis vesicles, but the effect was not observed with ovalbumin or keyhole limpet haemocyanin, demonstrating that this phenomenon is neither host-, microbe- nor protein-specific. Our findings strongly suggest that cryptococcal vesicles are short-lived in vivo and vesicle destabilization is mediated by albumin. The ability of albumin to promote vesicular offload through destabilization indicates a new activity for this abundant serum protein.


The usefulness of the GlideScope video laryngoscope in the education of conventional tracheal intubation for the novice.
The aim of this study is to evaluate the usefulness of the GlideScope video laryngoscope (GVL) as a tool to educate novice users in conventional tracheal intubation. 41 premedical students with no previous experience in tracheal intubation participated in this prospective, randomised and controlled study. Group M (n = 20) was instructed in tracheal intubation by using the Macintosh laryngoscope and group G (n = 21) was instructed by using both the GVL and the Macintosh laryngoscope. There was no significant difference in tracheal intubation performance using the Macintosh laryngoscope between the two groups. However, the GVL facilitates the education of tracheal intubation because it shows the same anatomical structure for both instructor and trainee simultaneously on a real-time basis. This aspect makes the trainee feel more comfortable learning the material with a high degree of satisfaction. Introducing GVL to conventional intubation education for novice users could increase the satisfaction of trainees during the procedure, especially as a way to understand critical anatomical structures.


Following the Reduction of Oxygen on TiO2 Anatase (101) Step by Step.
We have investigated the reaction between O2 and H2O, coadsorbed on the (101) surface of a reduced TiO2 anatase single crystal by scanning tunneling microscopy, density functional theory, temperature-programmed desorption, and X-ray photoelectron spectroscopy. While water adsorbs molecularly on the anatase (101) surface, the reaction with O2 results in water dissociation and formation of terminal OH groups. We show that these terminal OHs are the final and stable reaction product on reduced anatase. We identify OOH as a metastable intermediate in the reaction. The water dissociation reaction runs as long as the surface can transfer enough electrons to the adsorbed species; the energy balance and activation barriers for the individual reaction steps are discussed, depending on the number of electrons available. Our results indicate that the presence of donor dopants can significantly reduce activation barriers for oxygen reduction on anatase.


Reforming the provision of cross-border medical care: Evidence from Spain.
Cross-border medical care, defined as care facilitated by a local health provider under pre-established regional agreements, as in the case of European Union (EU) citizens accessing care within EU countries, has been on the rise. Unlike medical tourism, typically sought by patients through their own volition and paid for out-of-pocket, cross-border medical care is often reimbursable or paid for directly by the responsible government. Yet, because nations vary in the extent of health coverage offered to their residents, these expenditures are often only partially reimbursed. The resulting financial burden for some countries can be large and not reciprocal, straining regional and country-level finances. We analyze the effectiveness of a legislative measure adopted by a Spanish region in January 2012 with the purpose of curbing cross-border medical care. Using a comprehensive administrative dataset of all medical procedures performed in the country between 2008 and 2015, we find that the measure led to a drastic drop in the number of foreigners' hospitalizations and a reduction of 4.8 million euros/trimester in costs. Finally, the decrease in hospitalizations did not disproportionally affect patients based on their gender, age, or origin, although it fostered a reduction in readmissions.


Asymmetric nodal signaling in the zebrafish diencephalon positions the pineal organ.
The vertebrate brain develops from a bilaterally symmetric neural tube but later displays profound anatomical and functional asymmetries. Despite considerable progress in deciphering mechanisms of visceral organ laterality, the genetic pathways regulating brain asymmetries are unknown. In zebrafish, genes implicated in laterality of the viscera (cyclops/nodal, antivin/lefty and pitx2) are coexpressed on the left side of the embryonic dorsal diencephalon, within a region corresponding to the presumptive epiphysis or pineal organ. Asymmetric gene expression in the brain requires an intact midline and Nodal-related factors. RNA-mediated rescue of mutants defective in Nodal signaling corrects tissue patterning at gastrulation, but fails to restore left-sided gene expression in the diencephalon. Such embryos develop into viable adults with seemingly normal brain morphology. However, the pineal organ, which typically emanates at a left-to-medial site from the dorsal diencephalic roof, becomes displaced in position. Thus, a conserved signaling pathway regulating visceral laterality also underlies an anatomical asymmetry of the zebrafish forebrain.


A penalized regression framework for building polygenic risk models based on summary statistics from genome-wide association studies and incorporating external information.
Large-scale genome-wide association (GWAS) studies provide opportunities for developing genetic risk prediction models that have the potential to improve disease prevention, intervention or treatment. The key step is to develop polygenic risk score (PRS) models with high predictive performance for a given disease, which typically requires a large training data set for selecting truly associated single nucleotide polymorphisms (SNPs) and estimating effect sizes accurately. Here, we develop a comprehensive penalized regression for fitting l 1 regularized regression models to GWAS summary statistics. We propose incorporating Pleiotropy and ANnotation information into PRS (PANPRS) development through suitable formulation of penalty functions and associated tuning parameters. Extensive simulations show that PANPRS performs equally well or better than existing PRS methods when no functional annotation or pleiotropy is incorporated. When functional annotation data and pleiotropy are informative, PANPRS substantially outperforms existing PRS methods in simulations. Finally, we applied our methods to build PRS for type 2 diabetes and melanoma and found that incorporating relevant functional annotations and GWAS of genetically related traits improved prediction of these two complex diseases.


Study of the impact of land use and hydrogeological settings on the shallow groundwater quality in a peri-urban area of Kampala, Uganda.
A study to assess the impacts of land use and hydrogeological characteristics on the shallow groundwater in one of Kampala's peri-urban areas (Bwaise III Parish) was undertaken for a period of 19 months. Water quality monitoring was carried out for 16 installed wells and one operational protected spring to ascertain the seasonal variation. The aspects of hydrogeological setting investigated in the study were the subsurface unconsolidated material characteristics (stratigraphy, lithology, hydraulic conductivity, porosity and chemical content), seasonal groundwater depths and spring discharge, topography and rainfall of the area. Both laboratory and field measurements were carried out to determine the soil and water characteristics. Field surveys were also undertaken to identify and locate the various land use activities that may potentially pollute. The results demonstrate that the water table in the area responds rapidly to short rains (48 h) due to the pervious (10(-5)-10(-3) ms(-1)) and shallow (<1 mbgl) vadose zone, which consists of foreign material (due to reclamation). This anthropogenically influenced vadose zone has a limited contaminant attenuation capacity resulting in water quality deterioration following the rains. There is widespread contamination of the groundwater with high organic (up to 370 mgTKN/l and 779 mgNO-3/l), thermotolerant coliforms (TTCs) and faecal streptococci (FS) (median values as high as 126E3 cfu/100 ml and 154E3 cfu/100 ml respectively) and total phosphorus (up to 13 mg/l) levels originating from multiple sources of contamination. These include animal rearing, solid waste dumping, pit latrine construction and greywater/stormwater disposal in unlined channels leading to increased localised microbial (faecal) and organic (TKN/NO-3) contamination during the rains. The spring discharge (range 1.22-1.48 m3/h) with high nitrate levels (median values of 117 and 129 mg/l in the wet and dry seasons) did not vary significantly with season (p=0.087) suggesting that this source is fed by regional base flow. However, the microbial quality deterioration observed in the spring discharge after a rain event (median values of 815TTCs cfu /100 ml and 433 FS cfu/100 ml) was attributed to the poor maintenance of the protection structure. Identification and selection of appropriate management solutions for the protection of shallow groundwater in informal settlements should not only be based on water quality problems and the causal physical characteristics as demonstrated by this study, but also institutional and socio-economic factors.


'Metabolically healthy obesity': origins and implications.
When humans eat more and exercise less, they tend to become obese and unhealthy. The molecular pathways that link obesity to serious diseases like Type 2 diabetes and cardiovascular disease have become a subject of intensive scientific investigation because the exploding prevalence of obesity worldwide represents a grave new threat to the health of hundreds of millions of people. However, obesity is not always destiny. Two important clinical populations have been valuable to understand the mechanisms behind this conundrum: individuals who exhibit metabolic dysfunction, diabetes and elevated cardiovascular disease risk despite a lean body type, and individuals who are relatively protected from these dangers despite significant obesity. Study of this second group of 'metabolically healthy obese' people in particular has been revealing because such individuals exhibit specific, identifiable, anatomic, cellular and molecular features that set them apart from the rest of us who suffer declining health with increasing weight. Here, we examine some of these features, including some mouse models that are informative of mechanism, and suggest hypotheses for further study, including the possibility that genes and pathways of the immune system might offer new diagnostic or therapeutic targets.


TLR7 contributes to the rapid progression but not to the overall fatal outcome of secondary pneumococcal disease following influenza A virus infection.
Increased risk for bacterial superinfections substantially contributes to the mortality caused by influenza A virus (IAV) epidemics. While the mechanistic basis for this lethal synergism is still insufficiently understood, immune modulation through the viral infection has been shown to be involved. Since the pattern-recognition receptor (PRR) toll-like receptor 7 (TLR7) is a major sensor for the viral genome, we studied how IAV recognition by TLR7 influences the development of secondary pneumococcal infection. In a mouse model of IAV, TLR7-deficient hosts induced a potent antiviral response and showed unchanged survival. In secondary pneumococcal infection during acute influenza, TLR7ko mice showed a fatal outcome similar to wild-type (WT) hosts, despite significantly delayed disease progression. Also, when bacterial superinfection occurred after virus clearance, WT and TLR7-deficient hosts showed similar mortality, even though we found the phagocytic activity of alveolar macrophages isolated from IAV-pre-infected hosts to be enhanced in TLR7ko over WT mice. Thus, we show that a virus-sensing PRR modulates the progression of secondary pneumococcal infection following IAV. However, the fatal overall outcome in WT as well as TLR7ko hosts suggests that processes distinct from TLR7-triggering override the contribution of this single PRR.


Local density and group size interacts with age and sex to determine direction and rate of social dispersal in a polygynous mammal.
Movement away from an area or social group in response to increasing density (density-dependent dispersal) is known for most species; why it evolves is fundamental to our understanding of ecology and evolution. However, we have yet to fully appreciate how individuals of varying conditions (e.g., age and sex) might differently consider effects of density (quorum) when deciding to disperse or not, and scale dependence in their sense of quorum. We tracked movements of all individuals of a naturalized population of feral horses (Equus ferus caballus; Sable Island National Park Reserve, Nova Scotia, Canada) during a period of rapid population growth (N increased from 375 to 484 horses from 2008 to 2010). Permanent dispersal from breeding groups (bands) was positively density dependent for all age and sex categories with respect to local density (horses/km(2), bounded by the 99th percentile of individual movements [8000 m]), but was negatively and positively density dependent for males and females, respectively, in relation to group (band) size. Dispersal was generally female biased, with the exception of foals which moved with their mothers (no sex effect), and for yearlings and subadults when band sizes were smaller than average, in which case males dispersed at higher rates than females. Dispersal distance was positively related to local density. We conclude that dispersal rate can be both positively and negatively density dependent for feral horses, contingent on the state of individuals and the scale at which quorum with respect to choosing to disperse or not is assessed. Scale effects and interactions of density-dependent and sex- and age-biased dispersal may have both ecological and evolutionary consequences through effects on resource and mate competition.


Telehealth Interventions to Support Self-Management of Long-Term Conditions: A Systematic Metareview of Diabetes, Heart Failure, Asthma, Chronic Obstructive Pulmonary Disease, and Cancer.
Self-management support is one mechanism by which telehealth interventions have been proposed to facilitate management of long-term conditions. The objectives of this metareview were to (1) assess the impact of telehealth interventions to support self-management on disease control and health care utilization, and (2) identify components of telehealth support and their impact on disease control and the process of self-management. Our goal was to synthesise evidence for telehealth-supported self-management of diabetes (types 1 and 2), heart failure, asthma, chronic obstructive pulmonary disease (COPD) and cancer to identify components of effective self-management support. We performed a metareview (a systematic review of systematic reviews) of randomized controlled trials (RCTs) of telehealth interventions to support self-management in 6 exemplar long-term conditions. We searched 7 databases for reviews published from January 2000 to May 2016 and screened identified studies against eligibility criteria. We weighted reviews by quality (revised A Measurement Tool to Assess Systematic Reviews), size, and relevance. We then combined our results in a narrative synthesis and using harvest plots. We included 53 systematic reviews, comprising 232 unique RCTs. Reviews concerned diabetes (type 1: n=6; type 2, n=11; mixed, n=19), heart failure (n=9), asthma (n=8), COPD (n=8), and cancer (n=3). Findings varied between and within disease areas. The highest-weighted reviews showed that blood glucose telemonitoring with feedback and some educational and lifestyle interventions improved glycemic control in type 2, but not type 1, diabetes, and that telemonitoring and telephone interventions reduced mortality and hospital admissions in heart failure, but these findings were not consistent in all reviews. Results for the other conditions were mixed, although no reviews showed evidence of harm. Analysis of the mediating role of self-management, and of components of successful interventions, was limited and inconclusive. More intensive and multifaceted interventions were associated with greater improvements in diabetes, heart failure, and asthma. While telehealth-mediated self-management was not consistently superior to usual care, none of the reviews reported any negative effects, suggesting that telehealth is a safe option for delivery of self-management support, particularly in conditions such as heart failure and type 2 diabetes, where the evidence base is more developed. Larger-scale trials of telehealth-supported self-management, based on explicit self-management theory, are needed before the extent to which telehealth technologies may be harnessed to support self-management can be established.


Philanthropic conference-based requirements engineering in time of pandemic and beyond.
As software engineering (SE) practitioners, we can help society by using our communities of experts to address a software need of a socially conscious organization. Doing so can benefit society in the locale of a SE conference and provide access to international experts for local organizations. Furthermore, established SE researchers as well as practitioners and students have the opportunity for a unique learning experience. While the SE community has already realized the importance of addressing human values and promoting social good objectives in software development, we are unaware of previous attempts to leverage SE conferences for this activity. Conferences present an opportunity to enjoy the assembly of SE practitioners, researchers, and students for the purpose of a philanthropic endeavor. Over the past four years of running a "Requirements Engineering for Social Good" event called RE Cares, co-located with the International Conference on Requirements Engineering, we worked with the stakeholders local to the conference venue. We selected stakeholders who would not necessarily have ready access to requirements engineering, software design, and development expertise otherwise, to build software targeting "good causes." In the last two years, this event was altered to adapt to the constraints induced by COVID-19, moving to a hybrid mode and changing many of its practices accordingly. This paper summarizes and generalizes our experiences, discussing our lessons learned in the context of the pandemic and beyond and providing a framework for conducting similar social contribution in any SE conferences in general.


Gonadotropin-inhibiting hormone stimulates feeding behavior in chicks.
Neuropeptides containing a C-terminal Arg-Phe-NH2 motif (RFamide peptides) are suggested to be involved in the control of feeding behavior in both invertebrates and vertebrates. Gonadotropin-inhibitory hormone (GnIH) is the first identified avian RFamide peptide that inhibits gonadotropin release from the pituitary. The GnIH precursor encodes one GnIH and its related peptides (GnIH-RP-1 and -RP-2) that shared the same C-terminal motif, Leu-Pro-Xaa-Arg-Phe-NH2 (Xaa = Leu or Gln) (LPXRFamide). GnIH neurons are localized in the paraventricular nucleus, with their fibers visible in multiple brain locations including the median eminence and brainstem. In this study, we therefore investigated the action of GnIH and its related peptides on feeding behavior. Intracerebroventricular (ICV) injection of GnIH, GnIH-RP-1 and GnIH-RP-2 significantly stimulated food intake in chicks. The chicken pentapeptide LPLRFamide, a degraded C-terminus of GnIH and GnIH-RP-1, did not stimulate feeding thereby demonstrating the importance of the N-terminus of GnIH and its related peptides for the orexigenic effect. Anti-GnIH antiserum suppressed appetite induced by fasting, but did not modify feeding under ad libitum conditions. The present study suggests that GnIH and its related peptides act as endogenous orexigenic factors in the brain of chicks.


Somatic POLE exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response.
Genomic instability, which is a hallmark of cancer, is generally thought to occur in the middle to late stages of tumourigenesis, following the acquisition of permissive molecular aberrations such as TP53 mutation or whole genome doubling. Tumours with somatic POLE exonuclease domain mutations are notable for their extreme genomic instability (their mutation burden is among the highest in human cancer), distinct mutational signature, lymphocytic infiltrate, and excellent prognosis. To what extent these characteristics are determined by the timing of POLE mutations in oncogenesis is unknown. Here, we have shown that pathogenic POLE mutations are detectable in non-malignant precursors of endometrial and colorectal cancer. Using genome and exome sequencing, we found that multiple driver mutations in POLE-mutant cancers show the characteristic POLE mutational signature, including those in genes conventionally regarded as initiators of tumourigenesis. In POLE-mutant cancers, the proportion of monoclonal predicted neoantigens was similar to that in other cancers, but the absolute number was much greater. We also found that the prominent CD8+ T-cell infiltrate present in POLE-mutant cancers was evident in their precursor lesions. Collectively, these data indicate that somatic POLE mutations are early, quite possibly initiating, events in the endometrial and colorectal cancers in which they occur. The resulting early onset of genomic instability may account for the striking immune response and excellent prognosis of these tumours, as well as their early presentation. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Identifying Maternal Depression in Pediatric Primary Care: Changes Over a Decade.
Maternal depression affects 10% to 40% of mothers with young children and has negative consequences for children's health and development. The American Academy of Pediatrics (AAP) recommends that pediatricians identify women with maternal depression. The authors examined trends in inquiring about (asking informal questions) or screening for (using a standardized instrument) maternal depression by pediatricians in 2004 and 2013 and identified correlates of usually inquiring/screening to identify maternal depression. Data were ascertained from 778 nontrainee pediatricians exclusively practicing general pediatrics who completed the 2004 (n = 457) and 2013 (n = 321) AAP Periodic Surveys. Pediatricians answered questions about physician and practice characteristics, training, attitudes, and inquiring/screening to identify maternal depression. Sample weights were used to reduce nonresponse bias. Weighted descriptive and logistic regression analyses were conducted. The prevalence of usually inquiring/screening to identify maternal depression increased from 33% to 44% (p < .01). In both years, pediatricians who usually inquired about child/adolescent depression had increased odds of usually inquiring/screening to identify maternal depression. Patient race/ethnicity and training in adult Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnostic criteria for depression were associated with inquiring/screening in 2004, and believing that family screening is within the scope of the pediatrician was associated with inquiring/screening in 2013. Although inquiring/screening about maternal depression has increased since 2004, less than half of pediatricians usually screen or inquire about maternal depression, representing a missed opportunity to identify depression and manage or refer women for treatment. Further training on the importance of mental and family health to children's health may increase identification of maternal depression in pediatric primary care.


Somatotopic organization of gentle touch processing in the posterior insular cortex.
A network of thin (C and A delta) afferents relays various signals related to the physiological condition of the body, including sensations of gentle touch, pain, and temperature changes. Such afferents project to the insular cortex, where a somatotopic organization of responses to noxious and cooling stimuli was recently observed. To explore the possibility of a corresponding body-map topography in relation to gentle touch mediated through C tactile (CT) fibers, we applied soft brush stimuli to the right forearm and thigh of a patient (GL) lacking A beta afferents, and six healthy subjects during functional magnetic resonance imaging (fMRI). For improved fMRI analysis, we used a highly sensitive multivariate voxel clustering approach. A somatotopic organization of the left (contralateral) posterior insular cortex was consistently demonstrated in all subjects, including GL, with forearm projecting anterior to thigh stimulation. Also, despite denying any sense of touch in daily life, GL correctly localized 97% of the stimuli to the forearm or thigh in a forced-choice paradigm. The consistency in activation patterns across GL and the healthy subjects suggests that the identified organization reflects the central projection of CT fibers. Moreover, substantial similarities of the presently observed insular activation with that described for noxious and cooling stimuli solidify the hypothesized sensory-affective role of the CT system in the maintenance of physical well-being as part of a thin-afferent homeostatic network.


A small acidic protein 1 (SMAP1) mediates responses of the Arabidopsis root to the synthetic auxin 2,4-dichlorophenoxyacetic acid.
2,4-dichlorophenoxyacetic acid (2,4-D), a chemical analogue of indole-3-acetic acid (IAA), is widely used as a growth regulator and exogenous source of auxin. Because 2,4-D evokes physiological and molecular responses similar to those evoked by IAA, it is believed that they share a common response pathway. Here, we show that a mutant, antiauxin resistant1 (aar1), identified in a screen for resistance to the anti-auxin p-chlorophenoxy-isobutyric acid (PCIB), is resistant to 2,4-D, yet nevertheless responds like the wild-type to IAA and 1-napthaleneacetic acid in root elongation and lateral root induction assays. That the aar1 mutation alters 2,4-D responsiveness specifically was confirmed by analysis of GUS expression in the DR5:GUS and HS:AXR3NT-GUS backgrounds, as well as by real-time PCR quantification of IAA11 expression. The two characterized aar1 alleles both harbor multi-gene deletions; however, 2,4-D responsiveness was restored by transformation with one of the genes missing in both alleles, and the 2,4-D-resistant phenotype was reproduced by decreasing the expression of the same gene in the wild-type using an RNAi construct. The gene encodes a small, acidic protein (SMAP1) with unknown function and present in plants, animals and invertebrates but not in fungi or prokaryotes. Taken together, these results suggest that SMAP1 is a regulatory component that mediates responses to 2,4-D, and that responses to 2,4-D and IAA are partially distinct.


Risk stratification by p16 immunostaining of CIN1 biopsies: a retrospective study of patients from the quadrivalent HPV vaccine trials.
Previous studies of p16 immunohistochemistry (IHC) on CIN1 have suggested the likely utility of p16 in stratification of women at risk for subsequent CIN2/3. But those studies had limitations in statistical power, histologic diagnosis, and disease ascertainment. We conducted a retrospective study of p16 IHC on adjudicated CIN1 tissue diagnosed in young women participating in the placebo arm of the quadrivalent human papillomavirus (HPV) vaccine trials. Tissue sections were stained with p16 IHC and hematoxylin and eosin. p16 IHC was scored using LAST criteria, and hematoxylin and eosin-stained sections were reviewed for concordance with the adjudicated diagnosis. p16 IHC, antecedent high-grade cytology, review diagnosis, and HPV16 detection were assessed as independent risk factors for subsequent CIN2/3. Five hundred twenty-four patients with CIN1 biopsies and complete data were identified, 63 (12.0%) of whom developed CIN2/3 in follow-up. p16 positivity (P=0.06), review diagnosis of CIN2/3 (P=0.04), HPV16 positivity (P=0.01), and antecedent high-grade cytology (P=0.02) were (marginally) associated with CIN2/3. In a logistic regression model, the associations with CIN2/3 (vs. other), expressed as odds ratios (95% confidence intervals), were 1.6 (0.91-2.8) for p16, 2.0 (1.0-3.7) for HPV16, and 2.2 (1.1-2.4) for antecedent high-grade cytology. The mean risks for CIN2/3 estimated from the model ranged from 7.6% for negative for all markers to 36.3% for positive for all 3 markers. p16 IHC does not risk stratify CIN1 patients in a manner that would alter recommended management for CIN1. This reinforces the LAST recommendations that p16 should only be used selectively for problematic scenarios, such as CIN2 because of its inherent lack of reproducibility, cases in which one is struggling between CIN1 and CIN2, and benign mimics of CIN3.


HDR syndrome: a follow-up genotype-phenotype analysis of a de novo missense Thr272Ile mutation in exon 4 of GATA3.
Hypoparathyroidism, sensorineural deafness and renal dysplasia (HDR) syndrome (MIM 146255) is a rare autosomal dominant disorder caused by mutations in the gene encoding GATA3, a dual zinc-finger transcription factor involved in vertebrate embryonic development. In this clinical case study we report on a follow-up of a phenotype associated with a GATA3 mutation. HDR syndrome was clinically diagnosed at age of 1.5 years in a boy with a de novo heterozygous missense (c.815C→T) mutation, Thr272Ile, in exon 4 of the GATA3 gene. Both parents were negative for Thr272Ile.At age of 17 months, the patient had a weight of 10.7, a body length of 78 cm, and a head circumference of 47.5 cm. By the age of 7 years, growth is age-appropriate, severe bilateral hearing loss (dB 60) was corrected by hearing aids. However, cognitive development (auditory sensory me-mory and language abilities) is at the lower ends of the test scores.In conclusion, a mildly impaired clinical course was achieved by the age of 7 years in a patient with HDR syndrome; this report adds to the body of data on genotype-phenotype analysis in HDR syndrome. ·


Distinct features of circulating microparticles and their relationship to clinical manifestations in systemic lupus erythematosus.
Characterization of the abundance, origin, and annexin V (AnxV)-binding capabilities of circulating microparticles (MPs) in SLE patients and healthy controls and to determine any associations with clinical parameters. Seventy unselected SLE patients and 29 sex- and age-matched healthy control subjects were included in the study. MPs were isolated from citrate-treated plasma and characterized by flow cytometry using AnxV or antibodies to platelet, leukocyte, or endothelial cell surface markers. SLE patients had significantly increased concentrations of AnxV-nonbinding (AnxV-) MPs (P<0.0001), while the concentrations of total MPs (P=0.011) and AnxV-binding (AnxV+) MPs (P<0.0001) were decreased, as compared with controls. Based on flow cytometric characteristics, 2 subgroups of AnxV- MPs could be discerned: AnxV- cell-derived MPs (CDMPs) and AnxV- MPs of unknown nature (UNMPs). Both fractions were significantly increased in SLE patients (P=0.007 and P=0.0018, respectively). Platelet- and leukocyte-derived MPs were decreased in the SLE patients (P<0.0001), whereas no difference was observed for endothelial cell-derived MPs (P=0.14). The concentrations of AnxV- CDMPs correlated with the concentrations of endothelial cell-derived MPs, the disease activity score, active nephritis, hypertension, history of arterial thrombosis, and triglyceride levels (P<0.05 for all comparisons). The concentrations and composition of MPs in SLE patients differ markedly from those in healthy subjects. Overall MP numbers were significantly decreased, but two distinct subpopulations of AnxV- MPs were significantly increased. These findings call for further characterization of MPs in SLE patients to elucidate their role in disease pathogenesis.


Dissemination and persistence of extended-spectrum cephalosporin-resistance encoding IncI1-blaCTXM-1 plasmid among Escherichia coli in pigs.
This study investigated the ecology, epidemiology and plasmid characteristics of extended-spectrum cephalosporin (ESC)-resistant E. coli in healthy pigs over a period of 4 years (2013-2016) following the withdrawal of ESCs. High carriage rates of ESC-resistant E. coli were demonstrated in 2013 (86.6%) and 2014 (83.3%), compared to 2015 (22%) and 2016 (8.5%). ESC resistance identified among E. coli isolates was attributed to the carriage of an IncI1 ST-3 plasmid (pCTXM1-MU2) encoding blaCTXM-1. Genomic characterisation of selected E. coli isolates (n = 61) identified plasmid movement into multiple commensal E. coli (n = 22 STs). Major STs included ST10, ST5440, ST453, ST2514 and ST23. A subset of the isolates belong to the atypical enteropathogenic E. coli (aEPEC) pathotype that harboured multiple LEE pathogenic islands. pCTXM1-MU2 was similar (99% nt identity) to IncI1-ST3 plasmids reported from Europe, encoded resistance to aminoglycosides, sulphonamides and trimethoprim, and carried colicin Ib. pCTXM1-MU2 appears to be highly stable and readily transferable. This study demonstrates that ESC resistance may persist for a protracted period following removal of direct selection pressure, resulting in the emergence of ESC-resistance in both commensal E. coli and aEPEC isolates of potential significance to human and animal health.


Challenges and prospects for implementation of community health volunteers' digital health solutions in Kenya: a qualitative study.
The value of digital health technologies in delivering vital health care interventions, especially in low resource settings is increasingly appreciated. We co-developed and tested a decision support mobile health (m-Health) application (app);with some of the forms used by Community Health Volunteers (CHVs) in Kenya to collect data and connected to health facilities. This paper explores the experiences of CHVs, health workers and members of Sub-County Health Management Teams following implementation of the project. Data were collected in December 2017 through in-depth interviews and focus group discussions with CHVs and key informant interviews with health care workers and health managers in Kamukunji sub-County of Nairobi, Kenya. Data coding and analysis was performed in NVivo 12. Regarding users and health managers' perceptions towards the system; three main themes were identified: 1) variations in use, 2) barriers to use and 3) recommendations to improve use. Health workers at the private facility and some CHVs used the system more than health workers at the public facilities. Four sub-themes under barriers to use were socio-political environment, attitudes and behaviour, issues related to the system and poor infrastructure. A prolonged health workers' strike, the contentious presidential election in the year of implementation, interrupted electricity supply and lack of basic electric fixtures were major barriers to use. Suggestions to improve usage were: 1) integration of the system with others in use and making it available on users' regular phones, and 2) explore sustainable motivation models to users as well as performance based remuneration. The findings reveal the importance of considering the readiness of information and communication technologies (ICT) users before rollout of ICT solutions. The political and sociocultural environment in which the innovation is to be implemented and integration of new solutions into existing ones is critical for success. As more healthcare delivery models are developed, harnessing the potential of digital technologies, strengthening health systems is critical as this provides the backbone on which such innovations draw support.


Prevalence of orthopaedic maladies in people who flyfish: an Internet-based survey.
In this study, we define the prevalence of back and joint pains in people who flyfish. We use the Internet as a source of data. Requests for participation were posted on flyfishing Web sites. Eighty-nine people were surveyed (E-mail group). A control group of 42 flyfishing club members participated (Club group). Epidemiologic information, flyfishing data, and location of pain were collected. Low back pain in the 131 participants was 59%. No differences between the two groups in location or prevalence were noted. Saltwater fishermen had the highest rates of shoulder and elbow pain (31%). Trout fishermen had the highest rate of wrist pain (31%). Warmwater anglers had the least leg (12%), elbow (12%), and shoulder pain (18%). These afflictions mirror reports for other recreational activities. Low back pain was the most prevalent complaint, followed by wrist/hand and shoulder. Flyfishing subtypes have different rates and locations of pain, explained by equipment and technique. This report defines use of the Internet as a data source for research.


Modeling host interactions with hepatitis B virus using primary and induced pluripotent stem cell-derived hepatocellular systems.
Hepatitis B virus (HBV) chronically infects 400 million people worldwide and is a leading driver of end-stage liver disease and liver cancer. Research into the biology and treatment of HBV requires an in vitro cell-culture system that supports the infection of human hepatocytes, and accurately recapitulates virus-host interactions. Here, we report that micropatterned cocultures of primary human hepatocytes with stromal cells (MPCCs) reliably support productive HBV infection, and infection can be enhanced by blocking elements of the hepatocyte innate immune response associated with the induction of IFN-stimulated genes. MPCCs maintain prolonged, productive infection and represent a facile platform for studying virus-host interactions and for developing antiviral interventions. Hepatocytes obtained from different human donors vary dramatically in their permissiveness to HBV infection, suggesting that factors--such as divergence in genetic susceptibility to infection--may influence infection in vitro. To establish a complementary, renewable system on an isogenic background in which candidate genetics can be interrogated, we show that inducible pluripotent stem cells differentiated into hepatocyte-like cells (iHeps) support HBV infection that can also be enhanced by blocking interferon-stimulated gene induction. Notably, the emergence of the capacity to support HBV transcriptional activity and initial permissiveness for infection are marked by distinct stages of iHep differentiation, suggesting that infection of iHeps can be used both to study HBV, and conversely to assess the degree of iHep differentiation. Our work demonstrates the utility of these infectious systems for studying HBV biology and the virus' interactions with host hepatocyte genetics and physiology.


Iridium anomaly in the upper devonian of the canning basin, Western australia.
A moderate iridium anomaly, about 20 times the local background, has been found in Upper Devonian rocks in the Canning Basin. It occurs at or near the Frasnian-Famennian boundary, which is known to be associated with a major massextinction event of global extent. The anomaly occurs in an extremely condensed limestone sequence laid down under quiet deepwater conditions. Its occurrence suggests a causal link with some form of meteoroid impact. Moreover, carbon isotope data indicate that a large reduction in biomass could have occurred at this level. However, the anomaly coincides with a stromatolite bed containing the fossil cyanobacterium Frutexites; iridium, platinum, iron, manganese, cobalt, arsenic, antimony, and cerium are preferentially concentrated in filaments of this organism, with concentrations ranging from two to five times that of the matrix. It is possible that Frutexites extracted these elements directly from seawater, without the need for their derivation from an extraterrestrial source.


TRPC1 expression and distribution in rat hearts.
Transient receptor potential canonical (TRPC) proteins have been identified as a family of plasma membrane calcium-permeable channels. TRPC proteins can be activated by various stimuli and act as cellular sensors in mammals. Stretch-activated ion channels (SACs) have been proposed to underlie cardiac mechano-electric feedback (MEF), although the molecular entity of SAC remains unknown. There is evidence suggesting that transient receptor potential canonical 1 (TRPC1) is a stretch-activated ion channel. As a non-selective cation channel, TRPC1 may cause stretch-induced depolarization and arrhythmia and thus may contribute to the MEF of the heart. In this study, we examined the expression patterns of TRPC1 in detail at both the mRNA and protein levels in rat hearts. We isolated total RNA from the left and right atria, and the left and right ventricles, and detected TRPC1 mRNA in these tissues using reverse-transcriptase polymerase chain reaction (RT-PCR). To study the protein localization and targeting, we performed immunohistochemistry and immunofluorescence labeling with the antibody against TRPC1. TRPC1 was detected in the cardiomyocytes of the ventricle and atrium at both the mRNA and protein levels. The cell membrane and T-tubule showed strong fluorescence labeling in the ventricular myocytes. Purkinje cells, the endothelial cells and smooth muscle cells of the coronary arterioles also displayed TRPC1 labeling. No TRPC1 was detected in fibroblasts. In conclusion, TRPC1 is widely expressed in the rat heart, including in working cells, Purkinje cells and vascular cells, suggesting that it plays an important role in the heart. The specific distribution pattern offered a useful insight into its function in adult rat ventricular cells. Further investigations are needed to clarify the role of TRPC1 in regulating cardiac activity, including cardiac MEF.


Parameter Estimation for Groundwater Models under Uncertain Irrigation Data.
The success of modeling groundwater is strongly influenced by the accuracy of the model parameters that are used to characterize the subsurface system. However, the presence of uncertainty and possibly bias in groundwater model source/sink terms may lead to biased estimates of model parameters and model predictions when the standard regression-based inverse modeling techniques are used. This study first quantifies the levels of bias in groundwater model parameters and predictions due to the presence of errors in irrigation data. Then, a new inverse modeling technique called input uncertainty weighted least-squares (IUWLS) is presented for unbiased estimation of the parameters when pumping and other source/sink data are uncertain. The approach uses the concept of generalized least-squares method with the weight of the objective function depending on the level of pumping uncertainty and iteratively adjusted during the parameter optimization process. We have conducted both analytical and numerical experiments, using irrigation pumping data from the Republican River Basin in Nebraska, to evaluate the performance of ordinary least-squares (OLS) and IUWLS calibration methods under different levels of uncertainty of irrigation data and calibration conditions. The result from the OLS method shows the presence of statistically significant (p < 0.05) bias in estimated parameters and model predictions that persist despite calibrating the models to different calibration data and sample sizes. However, by directly accounting for the irrigation pumping uncertainties during the calibration procedures, the proposed IUWLS is able to minimize the bias effectively without adding significant computational burden to the calibration processes.


Shall We Focus on the Eosinophil to Guide Treatment with Systemic Corticosteroids during Acute Exacerbations of COPD?: PRO.
In an era of precision medicine, it seems regressive that we do not use stratified approaches to direct treatment of oral corticosteroids during an exacerbation of chronic obstructive pulmonary disease (COPD). This is despite evidence suggesting that 40% of COPD patients have eosinophilic inflammation and this is an indicator of corticosteroid response. Treatments with oral corticosteroids are not always effective and not without harm, with significant and increased risk of hyperglycemia, sepsis, and fractures. Eosinophils are innate immune cells with an incompletely understood role in the pathology of airway disease. They are detected at increased levels in some patients and can be measured using non-invasive methods during states of exacerbation and stable periods. Despite the eosinophil having an unknown mechanism in COPD, it has been shown to be a marker of length of stay in severe hospitalized exacerbations, a predictor of risk of future exacerbation and exacerbation type. Although limited, promising data has come from one prospective clinical trial investigating the eosinophil as a biomarker to direct systemic corticosteroid treatment. This identified that there were statistically significant and clinically worsened symptoms in patients with low eosinophil levels who were prescribed prednisolone, demonstrating the potential utility of the eosinophil. In an era of precision medicine our patients' needs are best served by accurate diagnosis, correct identification of maximal treatment response and the abolition of harm. The peripheral blood eosinophil count could be used towards reaching these aims.


Characterizing the physical and genetic structure of the lodgepole pine × jack pine hybrid zone: mosaic structure and differential introgression.
Understanding the physical and genetic structure of hybrid zones can illuminate factors affecting their formation and stability. In north-central Alberta, lodgepole pine (Pinus contorta Dougl. ex Loud. var. latifolia) and jack pine (Pinus banksiana Lamb) form a complex and poorly defined hybrid zone. Better knowledge of this zone is relevant, given the recent host expansion of mountain pine beetle into jack pine. We characterized the zone by genotyping 1998 lodgepole, jack pine, and hybrids from British Columbia, Alberta, Saskatchewan, Ontario, and Minnesota at 11 microsatellites. Using Bayesian algorithms, we calculated genetic ancestry and used this to model the relationship between species occurrence and environment. In addition, we analyzed the ancestry of hybrids to calculate the genetic contribution of lodgepole and jack pine. Finally, we measured the amount of gene flow between the pure species. We found the distribution of the pine classes is explained by environmental variables, and these distributions differ from classic distribution maps. Hybrid ancestry was biased toward lodgepole pine; however, gene flow between the two species was equal. The results of this study suggest that the hybrid zone is complex and influenced by environmental constraints. As a result of this analysis, range limits should be redefined.


The trajectory of intrahelical lesion recognition and extrusion by the human 8-oxoguanine DNA glycosylase.
Efficient search for DNA damage embedded in vast expanses of the DNA genome presents one of the greatest challenges to DNA repair enzymes. We report here crystal structures of human 8-oxoguanine (oxoG) DNA glycosylase, hOGG1, that interact with the DNA containing the damaged base oxoG and the normal base G while they are nested in the DNA helical stack. The structures reveal that hOGG1 engages the DNA using different protein-DNA contacts from those observed in the previously determined lesion recognition complex and other hOGG1-DNA complexes. By applying molecular dynamics simulations, we have determined the pathways taken by the lesion and normal bases when extruded from the DNA helix and their associated free energy profiles. These results reveal how the human oxoG DNA glycosylase hOGG1 locates the lesions inside the DNA helix and facilitates their extrusion for repair.


Biallelic mutations in the ubiquitin ligase RFWD3 cause Fanconi anemia.
The WD40-containing E3 ubiquitin ligase RFWD3 has been recently linked to the repair of DNA damage by homologous recombination (HR). Here we have shown that an RFWD3 mutation within the WD40 domain is connected to the genetic disease Fanconi anemia (FA). An individual presented with congenital abnormalities characteristic of FA. Cells from the patient carrying the compound heterozygous mutations c.205_206dupCC and c.1916T>A in RFWD3 showed increased sensitivity to DNA interstrand cross-linking agents in terms of increased chromosomal breakage, reduced survival, and cell cycle arrest in G2 phase. The cellular phenotype was mirrored in genetically engineered human and avian cells by inactivation of RFWD3 or introduction of the patient-derived missense mutation, and the phenotype was rescued by expression of wild-type RFWD3 protein. HR was disrupted in RFWD3-mutant cells as a result of impaired relocation of mutant RFWD3 to chromatin and defective physical interaction with replication protein A. Rfwd3 knockout mice appear to have increased embryonic lethality, are subfertile, show ovarian and testicular atrophy, and have a reduced lifespan resembling that of other FA mouse models. Although RFWD3 mutations have thus far been detected in a single child with FA, we propose RFWD3 as an FA gene, FANCW, supported by cellular paradigm systems and an animal model.


Costs of acquiring phosphorus by vascular land plants: patterns and implications for plant coexistence.
Content Summary 1420 I. Introduction 1421 II. Root adaptations that influence P acquisition 1422 III. Costs of P acquisition: general 1423 IV. Costs of P acquisition that are independent of soil P concentrations 1423 V. Costs of P acquisition that increase as soil P concentrations decline 1424 VI. Discussion and conclusions 1424 Acknowledgements 1425 References 1425 SUMMARY: We compare carbon (and hence energy) costs of the different modes of phosphorus (P) acquisition by vascular land plants. Phosphorus-acquisition modes are considered to be mechanisms of plants together with their root symbionts and structures such as cluster roots involved in mobilising or absorbing P. Phosphorus sources considered are soluble and insoluble inorganic and organic pools. Costs include operating the P-acquisition mechanisms, and resource requirements to construct and maintain them. For most modes, costs increase as the relevant soil P concentration declines. Costs can thus be divided into a component incurred irrespective of soil P concentration, and a component describing how quickly costs increase as the soil P concentration declines. Differences in sensitivity of costs to soil P concentration arise mainly from how economically mycorrhizal fungal hyphae or roots that explore the soil volume are constructed, and from costs of exudates that hydrolyse or mobilise insoluble P forms. In general, modes of acquisition requiring least carbon at high soil P concentrations experience a steeper increase in costs as soil P concentrations decline. The relationships between costs and concentrations suggest some reasons why different modes coexist, and why the mixture of acquisition modes differs between sites.


Is cervical screening preventing adenocarcinoma and adenosquamous carcinoma of the cervix?
While the incidence of squamous carcinoma of the cervix has declined in countries with organised screening, adenocarcinoma has become more common. Cervical screening by cytology often fails to prevent adenocarcinoma. Using prospectively recorded cervical screening data in England and Wales, we conducted a population-based case-control study to examine whether cervical screening leads to early diagnosis and down-staging of adenocarcinoma. Conditional logistic regression modelling was carried out to provide odds ratios (ORs) and 95% confidence intervals (CIs) on 12,418 women with cervical cancer diagnosed between ages 30 and 69 and 24,453 age-matched controls. Of women with adenocarcinoma of the cervix, 44.3% were up to date with screening and 14.6% were non-attenders. The overall OR comparing women up to date with screening with non-attenders was 0.46 (95% CI: 0.39-0.55) for adenocarcinoma. The odds were significantly decreased (OR: 0.22, 95% CI: 0.15-0.33) in up to date women with Stage 2 or worse adenocarcinoma, but not for women with Stage1A adenocarcinoma 0.71 (95% CI: 0.46-1.09). The odds of Stage 1A adenocarcinoma was double among lapsed attenders (OR: 2.35, 95% CI: 1.52-3.62) compared to non-attenders. Relative to women with no negative cytology within 7 years of diagnosis, women with Stage1A adenocarcinoma were very unlikely to be detected within 3 years of a negative cytology test (OR: 0.08, 95% CI: 0.05-0.13); however, the odds doubled 3-5 years after a negative test (OR: 2.30, 95% CI: 1.67-3.18). ORs associated with up to date screening were smaller for squamous and adenosquamous cervical carcinoma. Although cytology screening is inefficient at preventing adenocarcinomas, invasive adenocarcinomas are detected earlier than they would be in the absence of screening, substantially preventing Stage 2 and worse adenocarcinomas.


Few-states models for three-photon absorption.
Few-states models are derived for the calculation of three-photon absorption matrix elements. Together with earlier derived few-states models for two-photon absorption, the models are evaluated against results from response theory calculations that provide the full sum-over-states values. It is demonstrated that not even for systems with charge-transfer character, where few-states models for two-photon absorption are in excellent agreement with response theory, do the models provide a quantitatively correct description for three-photon absorption. The convergence behavior, merits, and shortcomings of the models are elucidated in some detail. The role of various characteristics of the electronic structure, such as symmetry, charge transfer, and conjugation--important for the formation of a large three-photon cross section--is analyzed. As for two-photon absorption cross sections, it is essential to consider generalized few-states models also for three-photon absorption, that is, to account for dipolar directions and laser beam polarization. Despite their poor quantitative performance, it is argued that few-states models at times can be useful for interpretation purposes when applied to three-photon absorption.


A standard model for foveal detection of spatial contrast.
The ModelFest data set was created to provide a public source of data to test and calibrate models of foveal spatial contrast detection. It consists of contrast thresholds for 43 foveal achromatic contrast stimuli collected from each of 16 observers. We have fit these data with a variety of simple models that include one of several contrast sensitivity functions, an oblique effect, a spatial sensitivity aperture, spatial frequency channels, and nonlinear Minkowski summation. While we are able to identify one model, with particular parameters, as providing the lowest overall residual error, we also note that the differences among several good-fitting models are small. We find a strong reciprocity between the size of the spatial aperture and the value of the summation exponent: both are effective means of limiting the extent of spatial summation. The results demonstrate the power of simple models to account for the visibility of a wide variety of spatial stimuli and suggest that special mechanisms to deal with special classes of stimuli are not needed. But the results also illustrate the limited power of even this large data set to distinguish among similar competing models. We identify one model as a possible standard, suitable for simple theoretical and applied predictions.


Loss of epithelial membrane protein-2 expression confers an independent prognosticator in nasopharyngeal carcinoma: a cohort study.
To evaluate the expression of epithelial membrane protein-2 (EMP2) protein and its clinicopathological associations in patients with nasopharyngeal carcinoma. Retrospective population-based cohort study. This study was based on a biobank in Chi-Mei Medical Center (Tainan, Taiwan) from 1993 to 2002. Biopsies of 124 consecutive nasopharyngeal carcinoma patients without initial distant metastasis and treated with consistent guidelines were assessed. Immunoexpressions of EMP2 were analysed and the outcomes were correlated with clinicopathological features and patient survivals. Immunoexpressions of EMP2 were analyzed and the outcomes were correlated with clinicopathological features and patient survivals. Loss of EMP2 expression (49.2%) was correlated with advanced primary tumour (p=0.044), nodal status (p=0.045) and the 7th American Joint Committee on Cancer stage (p=0.027). In multivariate analyses, loss of EMP2 expression emerged as an independent prognosticator for worse disease-specific survival (DSS; p=0.015) and local recurrence-free survival (LRFS; p=0.030), along with the American Joint Committee on Cancer stages III-IV (p=0.034, DSS; p=0.023, LRFS). Loss of EMP2 expression is common and associated with adverse prognosticators and might confer tumour aggressiveness through hampering its interaction with specific membrane protein(s) and hence the downstream signal transduction pathway(s).


Double anterior chick limb buds and models for cartilage rudiment specification.
Most models for the specification of the skeletal elements in the developing limb bud are based on a chemical specification well before overt cartilage differentiation. By contrast, a physico-mechanical model proposes that the process of condensation--an early feature of cartilage differentiation--is itself the basis for patterning the elements. The models thus make quite different predictions as to when the rudiments are specified. Double anterior limb buds have been constructed at stages earlier than condensation, with the expectation that, if specification of the humerus occurs before cartilage condensation, then limbs containing two humeri should develop, since the presumptive humerus lies largely in the anterior region. The development of anterior and posterior parts, on their own, was in general, consistent with the fate map; both developed a humerus that was thinner than normal. Double anterior limbs developed two humeri in 28% of cases and a much thicker humerus in 39%. These results strongly support models based on an early specification of limb rudiments and cannot be accounted for by the physical model. Double anterior limbs in which the two parts were from different stages, developed such that a digit 3 could lie adjacent to the radius, giving further striking evidence for early specification and local autonomy of development.


Calmodulin distribution and Ca2+ transport in the erythrocytes of patients with essential hypertension.
The rate of calcium transport and calmodulin distribution in the erythrocytes of patients with essential hypertension were studied. In erythrocyte membranes subjected to calmodulin depletion by treatment with EGTA, both the affinity of the calcium pump for Ca2+ and its maximal activity were the same in normotensive and hypertensive patients. The addition of exogenous calmodulin to calmodulin-stripped membranes from erythrocytes of patients with essential hypertension resulted in a smaller increase of the maximal activity of the calcium pump and its affinity for Ca2+. The addition of calmodulin to erythrocyte membranes obtained without EGTA treatment resulted in a smaller increase of the maximal activity of the calcium pump only. There were no significant differences of calmodulin distribution (cytoplasmic concentration and size of the membrane-bound pool) between the erythrocytes of normotensive and hypertensive patients. It is suggested that alterations in the calcium pump activity of the erythrocyte membranes of patients with essential hypertension are related to the alteration of interaction between calmodulin and Mg2+, Ca2+-ATPase.


Arthrobacter ulcerisalmonis sp. nov., isolated from an ulcer of a farmed Atlantic salmon (Salmo salar), and emended description of the genus Arthrobacter sensu lato.
A Gram-stain positive, pleomorphic, oxidase-negative, non-motile isolate from the ulcer of a farmed Atlantic salmon (Salmo salar), designated strain T11bT, was subjected to a comprehensive taxonomic investigation. A comparative analysis of the 16S rRNA gene sequence showed highest similarities to the type strains of Pseudarthrobacter siccitolerans (98.1 %) and Arthrobacter methylotrophus and Pseudarthrobacter phenanthrenivorans (both 98.0 %). The highest ANI value observed between the assembled genome of T11bT and the publicly available Pseudarthrobacter and Arthrobacter type strain genomes were 81.15 and 80.99 %, respectively. The major respiratory quinone was menaquinone MK-9(H2). The polyamine pattern contained predominantly spermidine. The polar lipid profile consisted of the major lipids diphosphatidylglycerol, phosphatidylglycerol, monogalactosyl-diacylglycerol and dimannosylglyceride. Minor amouts of trimannosyldiacylglycerol and phosphatidylinositol were also detected. The peptidoglycan was of the type A3α l-Lys-l-Ser-l-Thr-l-Ala (A11.23). In the fatty acid profile, anteiso and iso branched fatty acids predominated (anteiso C15 : 0, iso C16 : 0, anteiso C17 : 0). Moderate to low DNA-DNA similarities, physiological traits as well as unique traits in the fatty acid pattern distinguished strain T11bT from the next related species. All these data point to the fact that strain T11bT represents a novel species of the genus Arthrobacter for which we propose the name Arthrobacter ulcerisalmonis sp. nov. The type strain is T11bT (=CIP 111621T=CCM 8854T=LMG 30632T=DSM 107127T).


[Kawasaki disease].
Kawasaki disease is a systemic acute vasculitis of unknown etiology. It is the leading cause of acquired heart disease in children in the USA. It occurs more frequently in boys and eighty percent of the cases occur in children under five years of age. The disease rarely occurs after eight years and it can affect children of all races, with higher incidence among Asian descendants. Kawasaki disease is characterized by fever, bilateral non-exudative conjunctivitis, redness and swelling of the tongue, lips and oral mucosa, abnormalities in the extremities, cervical lymph node, and polymorphic exanthema. Aneurysms and stenoses of coronary arteries occur in approximately 20 to 25% of untreated patients and subsequently can lead to acute myocardial infarction and sudden death. Treatment with intravenous immunoglobulin is effective and should be initiated early to prevent cardiac sequel. The development of diagnostic tests, more specific treatment approaches and prevention of this potentially fatal disease in children depends on continuous advances in the determination of its pathogenesis.


A Preliminary Study of Serum Apelin Levels in Patients with Head and Neck Cancer.
Treatment planning is primarily based on the tumor node metastasis (TNM) staging system for head and neck cancer (HNC). However, TNM does not give sufficient information about biological aggressiveness, treatment response, and prognosis. New molecular markers are needed for individualized cancer treatment. Apelin is a bioactive peptide and an endogenous ligand for the G protein-coupled receptor (APJ). Its expression is induced under hypoxic conditions. Apelin and its receptor APJ are important factors in physiological angiogenesis and may be novel targets for anti-angiogenic tumor therapies. This preliminary study aimed to investigate whether there was a difference in serum apelin levels between patients with HNC and control group and also to compare the serum apelin levels before and after radiotherapy. Twenty-two patients with HNC (patient group) and 30 healthy individuals (control group) were included in the study. In the patient group, blood samples were collected before and after radiotherapy. Serum apelin-36 levels were measured by enzyme-linked immunosorbent assay. Serum apelin-36 levels were significantly higher in patients with HNC than in the control group (p<0.001). Coverage of the measured apelin-36 levels showed a significant decrease after radiotherapy according to the levels before radiotherapy. There was no statistically significant difference between the groups (p>0.05). Apelin may be a potential therapeutic target and a novel biomarker. Additional studies are needed to reveal the relationships between serum apelin and radiotherapy in solid human tumors.


Spectrum of Fates: a new approach to the study of the developing zebrafish retina.
The ability to image cells live and in situ as they proliferate and differentiate has proved to be an invaluable asset to biologists investigating developmental processes. Here, we describe a Spectrum of Fates approach that allows the identification of all the major neuronal subtypes in the zebrafish retina simultaneously. Spectrum of Fates is based on the combinatorial expression of differently coloured fluorescent proteins driven by the promoters of transcription factors that are expressed in overlapping subsets of retinal neurons. Here, we show how a Spectrum of Fates approach can be used to assess various aspects of neural development, such as developmental waves of differentiation, neuropil development, lineage tracing and hierarchies of fates in the developing zebrafish retina.


Risk of venous thromboembolism in ankylosing spondylitis: a general population-based study.
Venous thromboembolism (VTE), including pulmonary embolism (PE) and deep venous thrombosis (DVT), can be life threatening. An increased frequency of VTE has been found in inflammatory conditions. To date, evidence assessing whether this risk is also greater in patients with ankylosing spondylitis (AS) is scarce. Using the provincial British Columbia, Canada healthcare database that encompasses all residents within the province, we conducted matched cohort analyses of incident PE, DVT and overall VTE among incident cases of AS and compared them with individuals randomly selected from the general population without AS. We calculated incidence rates (IRs) of VTE and multivariable analyses after adjusting for traditional risk factors using Cox models. Among 7190 incident cases of AS, 35 developed PE and 47 developed DVT. IRs of PE, DVT and overall VTE per 1000 person-years for patients with AS were 0.79, 1.06, 1.56 compared with 0.40, 0.50, 0.77 in the control cohort. Corresponding fully adjusted HRs (95% CI) of PE, DVT and VTE were 1.36 (0.92 to 1.99), 1.62 (1.16 to 2.26) and 1.53 (1.16 to 2.01), respectively. The risks of PE, DVT and VTE were highest in the first year of diagnosis with HR (95% CI) of 2.88 (0.87 to 9.62), 2.20 (0.80 to 6.03) and 2.10 (0.88 to 4.99), respectively. These findings demonstrate an increased risk of VTE in the general AS population. This risk appears the most prominent in the first year after diagnosis.


Therapeutic hypothermia for out-of-hospital cardiac arrest: implementation in a district general hospital emergency department.
The use of therapeutic hypothermia is recommended for unconscious adult patients with return of spontaneous circulation (ROSC) after out-of-hospital ventricular fibrillation cardiac arrest. There is evidence that the time taken to achieve target temperature impacts survival. To audit the performance of an emergency department (ED) in implementing therapeutic hypothermia and achieving target temperature in survivors of out-of-hospital cardiac arrest admitted to the intensive care unit (ICU). Data were extracted from the medical records of patients admitted to the ICU from the ED in the Royal United Hospital following out-of-hospital cardiac arrest (OHCA) between June 2002 and October 2008. The intervals between ROSC and initiation of cooling and between initiation of cooling and achieving the core temperature of 34°C were recorded. During this period, 83 patients were admitted to the ICU following OHCA. Of these, 67 (81%) were actively cooled. All 16 patients who were not cooled had recognised exclusion criteria. The median time (IQR) from ROSC to initiation of cooling was 60 (40-165) minutes and the median time (IQR) to reach 34°C was 175 (40-420) minutes. Of the 67 who were cooled, 44 (66%) achieved the temperature of 34°C within 4 h, the audit standard published by the Royal College of Anaesthetists. In 29 (43%) patients, the temperature increased after leaving the ED. Among OHCA patients who met recognised inclusion criteria, therapeutic hypothermia was implemented successfully by the ED staff. The temperature should be measured continuously from the same site in both the ED and the ICU. This will provide consistent and continuous temperature monitoring between the ED and the ICU and will enable prompt intervention to prevent temperature increases.


Pouchitis Is a Common Complication in Patients With Familial Adenomatous Polyposis Following Ileal Pouch-Anal Anastomosis.
Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the surgical procedure most commonly selected for patients with familial adenomatous polyposis (FAP) or ulcerative colitis that is refractive to medical treatment. Pouchitis is the most common complication in patients with ulcerative colitis after IPAA, but is thought to rarely occur in patients with FAP. We investigated the frequency of pouchitis and other pouch-related complications in patients with FAP after IPAA. We performed a retrospective cohort study of all patients with FAP who underwent IPAA at a single tertiary institution from 1992 through 2015 (n = 113). Patients were identified using International Classification of Diseases-9 diagnostic and current procedural terminology codes. We obtained relevant demographic and clinical data from patients' electronic medical records. The frequencies of pouchitis and pouch-related complications were determined. Twenty-five patients (22.1%) developed pouchitis (mean time to pouchitis, 4.1 years) and 88 did not (77.9%). Patients with pouchitis showed a trend toward developing late (>90 days after IPAA) pouch-related complications (56.0% of patients with pouchitis developed late complications, compared with 36.4% without). In patients who developed pouchitis, the disease course was acute in 72.0% and chronic in 28.0%. Of those treated, 69.6% responded to antibiotics, 13.0% became dependent on antibiotics, and 13.0% developed antibiotic resistance. Pouchitis is more prevalent in patients with FAP than previously believed. Although pouchitis seems to occur later in patients with FAP than in patients with ulcerative colitis, and have a milder course, it should be considered a common complication among patients with FAP following IPAA.


Update on the effects of physical activity on insulin sensitivity in humans.
This review presents established knowledge on the effects of physical activity (PA) on whole-body insulin sensitivity (SI) and summarises the findings of recent (2013-2016) studies. Recent studies provide further evidence to support the notion that regular PA reduces the risk of insulin resistance, metabolic syndrome and type 2 diabetes, and SI improves when individuals comply with exercise and/or PA guidelines. Many studies indicate a dose response, with higher energy expenditures and higher exercise intensities, including high intensity interval training (HIIT), producing greater benefits on whole-body SI, although these findings are not unanimous. Aerobic exercise interventions can improve SI without an associated increase in cardiorespiratory fitness as measured by maximal or peak oxygen consumption. Both aerobic and resistance exercise can induce improvements in glycaemic regulation, with some suggestions that exercise regimens including both may be more efficacious than either exercise mode alone. Some studies report exercise-induced benefits to SI that are independent of habitual diet and weight loss, while others indicate an association with fat reduction, hence the debate over the relative importance of PA and weight loss continues. During exercise, muscle contraction stimulated improvements in SI are associated with increases in AMPK activity, which deactivates TCB1D1, promoting GLUT4 translocation to the cell membrane and thereby increasing glucose uptake. Postexercise, increases in Akt deactivate TCB1D4 and thereby increase GLUT4 translocation to the cell membrane. The reduction in intramuscular saturated fatty acids and concomitant reductions in ceramides, but not diacylglycerols, provide a potential link between intramuscular lipid content and SI. Increased skeletal muscle capillarisation provides another independent adaptation through which SI is improved, as does enhanced β cell activity. Recent studies are combining exercise interventions with dietary and feeding manipulations to investigate the potential for augmenting the exercise-induced improvements in SI and glycaemic control.


Endoplasmic reticulum chaperone gp96 is required for innate immunity but not cell viability.
Chaperone proteins are thought to promote the correct folding and assembly of newly synthesized proteins and to facilitate restoration of the folded state under environmental conditions that favour protein denaturation. They are among the most ubiquitous and highly conserved of all proteins. The eukaryotic endoplasmic reticulum (ER) chaperone gp96 in particular has long been thought to be indispensable for cell survival. Here we report that a screen for genes required for the immune response to bacterial endotoxins has identified a B-cell line deficient in gp96. Absence of gp96 is compatible with cellular survival even under stress conditions and causes a defect in the formation of only a small subset of cell surface receptors. Toll-like receptors are retained intracellularly in the absence of gp96, explaining the unresponsiveness of the mutant to microbial stimuli.


Rapid rise and subsequent decline in prostate cancer incidence rates for New Mexico, 1989-1993.
Beginning in the late 1980s, a large increase in incidence rates for prostate cancer occurred in association with increased prostate-specific antigen (PSA) screening. In New Mexico, the increased screening was associated with earlier detection of cancers and decreased prostate cancer mortality, suggesting that PSA screening may be effective. PSA screening has become a controversial topic of public debate, and anecdotal reports from physicians indicated that prostate cancer screening practice patterns were changing in New Mexico. To assess whether PSA-associated trends in prostate cancer incidence were continuing, we examined incidence rates from 1989 to 1993 among men in New Mexico. From 1989 to 1992, age-adjusted rates increased substantially for non-Hispanic whites (77%), Hispanics (50%), and American Indians (27%). Although rates increased for all stages combined, incidence rates decreased for distant-stage disease, especially for non-Hispanic whites, indicating a continuing trend toward earlier detection. In 1993, incidence rates unexpectedly decreased from 203 to 158/100,000 in non-Hispanic whites, largely as a result of changes in rates in men over age 65 years. Although incidence rates decreased, the trend toward earlier detection was maintained for non-Hispanic whites. In contrast, among Hispanic and American Indians, rates did not change substantially between 1992 and 1993. Because the epidemic in prostate cancer was associated with increased PSA screening, it is likely that the trends for non-Hispanic whites are also related to PSA screening. We suggest that the decrease in rates and the continued stage shift are consistent with repeated screening of men in the population at risk.


A computational method for developing hierarchical large deformation viscoelastic models of the contracting heart.
In this study, a new computational method for modelling the contracting heart is described. Using this method, the cardiac wall is constructed from basic, repeating contractile units that represent individual myocardial units and collagen, each with its own set of parameters, including orientation, passive and active behaviour and stimulation propagation. The method allows individual control of each structural unit (e.g. at the level of a single myocardial unit). Feasibility of modelling dynamic heart contraction using this method is demonstrated using 2D cross-sections and simplified 3D geometries. Effects of non-contractile scar and myopathic tissue were also tested in these geometrical configurations. Results from the 2D and 3D simulations were, overall, in agreement with well-established physiological data. The present method holds promise for modelling complex heart pathologies, abnormal mechanical properties (e.g. myocardial infarcts) and electrical conduction properties (branch blocks), and their spatial distributions across the myocardial tissues.


A genomewide catalogue of single nucleotide polymorphisms in white-beaked and Atlantic white-sided dolphins.
The field of population genetics is rapidly moving into population genomics as the quantity of data generated by high-throughput sequencing platforms increases. In this study, we used restriction-site-associated DNA sequencing (RADSeq) to recover genomewide genotypes from 70 white-beaked (Lagenorhynchus albirostris) and 43 Atlantic white-sided dolphins (L. acutus) gathered throughout their north-east Atlantic distribution range. Both species are at a high risk of being negatively affected by climate change. Here, we provide a resource of 38,240 RAD-tags and 52,981 nuclear SNPs shared between both species. We have estimated overall higher levels of nucleotide diversity in white-sided (π = 0.0492 ± 0.0006%) than in white-beaked dolphins (π = 0.0300 ± 0.0004%). White-sided dolphins sampled in the Faroe Islands, belonging to two pods (N = 7 and N = 11), showed similar levels of diversity (π = 0.0317 ± 0.0007% and 0.0267 ± 0.0006%, respectively) compared to unrelated individuals of the same species sampled elsewhere (e.g. π = 0.0285 ± 0.0007% for 11 Scottish individuals). No evidence of higher levels of kinship within pods can be derived from our analyses. When identifying the most likely number of genetic clusters among our sample set, we obtained an estimate of two to four clusters, corresponding to both species and possibly, two further clusters within each species. A higher diversity and lower population structuring was encountered in white-sided dolphins from the north-east Atlantic, in line with their preference for pelagic waters, as opposed to white-beaked dolphins that have a more patchy distribution, mainly across continental shelves.


Calcitonin inhibition of prolactin secretion in isolated rat pituitary cells.
Salmon calcitonin inhibited TRH-stimulated release of prolactin in isolated pituitary cells from untreated female rats. These cells were still capable of responding to the fresh addition of TRH after the removal of calcitonin. Calcitonin gene-related peptide had only a weak effect in inhibiting prolactin release in these cells. Pituitary cells isolated from female rats which had been treated with weekly s.c. injections of 1 mg oestradiol dipropionate for 4 weeks, exhibited a marked increase in the magnitude of the inhibition of prolactin release by salmon calcitonin. Both basal and TRH-stimulated release of prolactin were inhibited by concentrations of 0.1 nmol salmon calcitonin/l or higher. Prolactin release from these cells was also inhibited at somewhat higher concentrations by calcitonin gene-related peptide. Our results demonstrate that calcitonin can directly inhibit basal as well as TRH-stimulated prolactin release by acting directly at the pituitary. The results strongly suggest that the peptide may be involved in the regulation of prolactin release in certain physiological conditions.


Multifunctional polyoxometalates encapsulated in MIL-100(Fe): highly efficient photocatalysts for selective transformation under visible light.
H3PMo12O40 molecules have been successfully encapsulated in the cavities of MIL-100(Fe) via a facile hydrothermal method (denoted as HPMo@MIL-100(Fe)). A series of characterization has corroborated the insertion of H3PMo12O40 within the cavities of MIL-100(Fe). The resulting HPMo@MIL-100(Fe) nanocomposites have exhibited much higher photoactivity than the original-MIL-100(Fe) toward the photocatalytic selective oxidation of benzylic alcohols and the reduction of Cr(vi) under visible light irradiation (λ≥ 420 nm). The higher photoactivity of HPMo@MIL-100(Fe) can be attributed to the integrative effect of enhanced light absorption intensity and more efficient separation of photogenerated electron-hole pairs. The host porous structure of MIL-100(Fe) can achieve a uniform composition with H3PMo12O40, which is significantly important for producing highly reactive dispersed H3PMo12O40 molecules and enhancing the photocatalytic activity of HPMo@MIL-100(Fe) nanocomposites. And the immobilized H3PMo12O40 molecules are more convenient for recycling. Importantly, almost no Fe and Mo ions leach from the MIL-100(Fe) during the reaction, which verifies the photostability of the HPMo@MIL-100(Fe). In addition, possible photocatalytic redox reaction mechanisms have been investigated.


Ion and polymer dynamics in polymer electrolytes PPO-LiClO4. I. Insights from NMR line-shape analysis.
We investigate ion and polymer dynamics in polymer electrolytes PPO-LiClO4 performing 2H and 7Li NMR line-shape analysis. Comparison of temperature dependent 7Li and 2H NMR spectra gives evidence for a coupling of ion and polymer dynamics. 2H NMR spectra for various salt concentrations reveal a strong slowdown of the polymer segmental motion when the salt content is increased. The 2H NMR line shape further indicates that the segmental motion is governed by dynamical heterogeneities. While the width of the distribution of correlation times G(log tau) is moderate for low and high salt content, an extremely broad distribution exists for an intermediate salt concentration of 15:1 PPO-LiClO4. For the latter composition, a weighted superposition of two spectral components, reflecting the fast and the slow polymer segments of the distribution, describes the 2H NMR line shape over a broad temperature range. Analysis of the temperature dependent relative intensity of both spectral components indicates the existence of a continuous rather than a discontinuous distribution G(log tau). Such continuous distribution is consistent with gradual fluctuations of the local salt concentration and, hence, of the local environments of the polymer segments, whereas it is at variance with the existence of large salt-depleted and salt-rich domains featuring fast and slow polymer dynamics, respectively. Finally, for all studied PPO-LiClO4 mixtures, the 2H NMR line shape strongly depends on the echo delay in the applied echo-pulse sequence, indicating that the structural relaxation of the polymer segments involves successive rotational jumps about small angles gamma < 20 degrees .


Ser-249 p53 mutations in plasma DNA of patients with hepatocellular carcinoma from The Gambia.
A selective mutation, an arginine-to-serine substitution in codon 249, of the p53 gene has been identified as a "hotspot" mutation in hepatocellular carcinoma (HCC). This mutation occurs in populations that are exposed to aflatoxins and have a high prevalence of hepatitis B virus carriers. We evaluated whether this mutation could be detected in cell-free DNA isolated from the plasma of subjects from The Gambia to detect this mutation that is strongly associated with HCC. Fifty-three patients with HCC, 13 patients with cirrhosis, and 53 control subjects were prospectively recruited from The Gambia. Sixty patients, of non-African origin, with various liver pathologies were also selected from France. DNA was extracted and purified from 200-microL aliquots of plasma. The Ser-249 p53 mutation was detected by restriction endonuclease digestion of polymerase chain reaction products from exon 7 and was confirmed by direct sequencing of the amplified DNA. The Ser-249 p53 mutation was detected in plasma DNA from 19 (36%) of the 53 patients with HCC, two (15%) of the 13 patients with cirrhosis, and three (6%) of the 53 control subjects. This mutation was not detected in any plasma DNA from the European patients. The adjusted odds ratio for having the mutation was 16.4 (95% confidence interval = 3.0-90.5) for patients with HCC compared with the control subjects. The Ser-249 p53 mutation in plasma DNA is strongly associated with HCC in Gambian patients. This mutation was also detected at a much lower prevalence in plasma DNA from Gambian patients with cirrhosis and in Gambian control subjects, findings that may lead to the earlier detection of HCC. Use of the Ser-249 p53 mutation should facilitate further molecular epidemiologic studies on the development of HCC.


Going beyond horizontal equity: an analysis of health expenditure allocation across geographic areas in Mozambique.
In contexts where health services are mostly publicly provided and access is still limited, health financing systems require some mechanism for distributing financial resources across geographic areas according to population need. Equity in public health expenditure has been evaluated either by comparing allocations across spending units to equitable shares established using resource allocation formulae, or by using benefit incidence analysis to look at the distribution of expenditure across individual service users. In the latter case, the distribution across individuals has typically not been linked to the mechanisms that determine the allocation across geographic areas, and to the utilization of specific services by individuals. In this paper, we apply benefit incidence analysis in an innovative way to assess horizontal and vertical equity in the geographic allocation of recurrent expenditure for outpatient health care across districts in Mozambique. We compare the actual distribution of expenditure with horizontal and vertical equity benchmarks, set according to measures of economic status and need for health care. We quantify the observed inequities and the relative contributions of service use and resource allocation. We analyse government and donor expenditure separately and combined, for the years 2008-2011 to compare changes over time and funding source. We use data from a number of national routine sources. Results show improvements in both horizontal and vertical equity, along with the gradual alignment of government and donor resources over time, which resulted in almost horizontally and vertically equitable resource allocation in 2011. However, inequities in the distribution of expenditure across beneficiaries persisted and were driven by inequities in service use. The discrepancy between economic and need indicators highlighted initial differences in government and donor expenditure targets, raising questions about the purpose of public health expenditure and confirming the importance of clearly defining equity objectives to inform and evaluate resource allocation policies.


Histamine release and circulating cells after antigen inhalation in allergic dogs.
Histamine can be recovered from the blood of ragweed-sensitized dogs after aerosol antigen challenge, although its source is unknown. Neutrophils and eosinophils have been recovered from bronchoalveolar lavage fluid (BALF) obtained under identical conditions. We investigated the time course of changes in histamine levels in plasma and BALF taken from ragweed-sensitized dogs after aerosol challenge. Changes in the numbers of circulating neutrophils, eosinophils, lymphocytes, monocytes, and platelets were also studied. After 3 min, total pulmonary resistance (RL) was maximally increased and systolic blood pressure was maximally decreased. Histamine levels in plasma and BALF were increased and circulating eosinophils and neutrophils were decreased. After 15 min, platelet numbers were reduced. By 90 min, changes in RL, blood pressure, plasma and BALF histamine concentrations, and circulating neutrophils and eosinophils had returned to base-line values, but platelet numbers remained significantly decreased. Sham challenge caused no significant changes in any of these variables. Intravenous administration of histamine in doses large enough to attain plasma levels comparable with those achieved after aerosol antigen challenge resulted in no concomitant rise in BALF histamine levels. We conclude that antigen challenge in sensitized dogs causes increases in BALF and plasma histamine levels and is associated with a reduction in circulating neutrophils, eosinophils, and platelets. It is likely that antigen causes airway mast cells to release mediators that move down a concentration gradient from the airways to the pulmonary circulation.


FRET or no FRET: a quantitative comparison.
Fluorescence resonance energy transfer (FRET) is a technique used to measure the interaction between two molecules labeled with two different fluorophores (the donor and the acceptor) by the transfer of energy from the excited donor to the acceptor. In biological applications, this technique has become popular to qualitatively map protein-protein interactions, and in biophysical projects it is used as a quantitative measure for distances between a single donor and acceptor molecule. Numerous approaches can be found in the literature to quantify and map FRET, but the measures they provide are often difficult to interpret. We propose here a quantitative comparison of these methods by using a surface FRET system with controlled amounts of donor and acceptor fluorophores and controlled distances between them. We support the system with a Monte Carlo simulation of FRET, which provides reference values for the FRET efficiency under various experimental conditions. We validate a representative set of FRET efficiencies and indices calculated from the different methods with different experimental settings. Finally, we test their sensitivity and draw conclusions for the preparation of FRET experiments in more complex and less-controlled systems.