Effects of time since fire on birds: how informative are generalized fire response curves for conservation management?
Fire is both a widespread natural disturbance that affects the distribution of species and a tool that can be used to manage habitats for species. Knowledge of temporal changes in the occurrence of species after fire is essential for conservation management in fire-prone environments. Two key issues are: whether postfire responses of species are idiosyncratic or if multiple species show a limited number of similar responses; and whether such responses to time since fire can predict the occurrence of species across broad spatial scales. We examined the response of bird species to time since fire in semiarid shrubland in southeastern Australia using data from surveys at 499 sites representing a 100-year chronosequence. We used nonlinear regression to model the probability of occurrence of 30 species with time since fire in two vegetation types, and compared species' responses with generalized response shapes from the literature. The occurrence of 16 species was significantly influenced by time since fire: they displayed six main responses consistent with generalized response shapes. Of these 16 species, 15 occurred more frequently in mid- or later-successional vegetation (> 20 years since fire), and only one species occurred more often in early succession (< 5 years since fire). The models had reasonable predictive ability for eight species, some predictive ability for seven species, and were little better than random for one species. Bird species displayed a limited range of responses to time since fire; thus a small set of fire ages should allow the provision of habitat for most species. Postfire successional changes extend for decades and management of the age class distribution of vegetation will need to reflect this timescale. Response curves revealed important seral stages for species and highlighted the importance of mid- to late-successional vegetation (> 20 years). Although time since fire clearly influences the distribution of numerous bird species, predictive models of the spatial distribution of species in fire-prone landscapes need to incorporate other factors in addition to time since fire.


Identification of Cofilin-1 Induces G0/G1 Arrest and Autophagy in Angiotensin-(1-7)-treated Human Aortic Endothelial Cells from iTRAQ Quantitative Proteomics.
The angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis is a pathway that acts against the detrimental effects of the renin-angiotensin system. However, the effects of angiotensin-(1-7) on endothelial protein expression and the related phenotypes are unclear. We performed a duplicate of iTRAQ quantitative proteomic analysis on human aortic endothelial cells (HAECs) treated with angiotensin-(1-7) for 6 hours. Cofilin-1 was identified as a highly abundant candidate with consistent >30% coverage and >1.2-fold overexpression in the angiotensin-(1-7)-treated group. Gene ontology analysis showed that the "regulation_of_mitosis" was significantly altered, and cell cycle analysis indicated that the 6-hour angiotensin-(1-7) treatment significantly induced G0/G1 arrest. Knockdown of the cofilin-1 (CFL1) gene suggested the G0/G1 phase arrest was mediated by the modulation of p27 and the p21/Cyclin/CDK complex by Cofilin-1. Interestingly, quiescent HAECs escaped G0/G1 arrest upon angiotensin-(1-7) treatment for 24 hours, and angiotensin-(1-7) induced autophagy by upregulating Beclin-1 and microtubule-associated protein 1 light chain 3b-II expression, which was also attenuated by A779 pre-treatment and CFL1 knockdown. After pre-treatment with 3-methyladenine (3MA), treatment with angiotensin-(1-7) for 24 h induced significant G0/G1 phase arrest and apoptosis, suggesting a pro-survival role of autophagy in this context. In conclusion, Cofilin-1 plays a dominant role in angiotensin-(1-7)-induced G0/G1 arrest and autophagy to maintain cellular homeostasis in HAECs.


Inhibition of quorum-sensing-controlled virulence factors of Pseudomonas aeruginosa by Murraya koenigii essential oil: a study in a Caenorhabditis elegans infectious model.
The global emergence of antibiotic-resistant strains of Pseudomonas aeruginosa poses a major threat in both hospital environments and the community. P. aeruginosa is an opportunistic human pathogen, and it also infects a wide range of model organisms including the nematode Caenorhabditis elegans. Quorum sensing (QS) mediates cell-to-cell communication in bacteria and has an important role in regulating virulence genes, antibiotic resistance and biofilm formation, which are crucial for establishment of the infection. Expression of many virulence factors such as pyocyanin and proteases in P. aeruginosa is under the control of the QS system, and are mediated by small molecules such as acyl homoserine lactones. Thus, interfering with the QS system would provide alternative ways of controlling the pathogenicity. Murraya koenigii is a medicinal plant widely used in India. The present study investigated the in vivo inhibitory activity of M. koenigii essential oil (EO) on QS-controlled virulence factors of P. aeruginosa PAO1 using C. elegans. M. koenigii EO significantly inhibited the pyocyanin production and staphylolytic LasA activity of P. aeruginosa PAO1. As compared to the control group with 100 % killing of C. elegans, M. koenigii EO was able to rescue an average of 60 % of C. elegans from death due to the toxic effect of P. aeruginosa. Thus, the present study suggests the anti-QS potential of M. koenigii EO which therefore can be considered as a future therapeutic agent for management of P. aeruginosa-mediated infections.


Associations of Neighborhood Environmental Attributes with Walking in Japan: Moderating Effects of Area-Level Socioeconomic Status.
Several studies have examined how the associations of built environment attributes with walking behaviors may be moderated by socioeconomic status (SES). Such understanding is important to address socioeconomic inequalities in health through urban design initiatives. However, to date, there is no study examining the moderation effects of SES in the relationships of environmental attributes and walking in non-Western countries. The current study aims to examine associations of environmental attributes with walking behaviors among Japanese adults, and to test whether these associations were moderated by area-level SES. Data on walking were collected from Japanese adults using a nationwide Internet survey (N = 4605). Built environment measures including population density, street density, distance to the nearest public open space, and distance to the nearest commercial destination were calculated using geographic information systems software. An index of neighborhood deprivation was used as an area-level indicator of SES. Logistic regression models adjusted for clustering and sociodemographic variables were used. It was found that more residents in high SES areas walked for commuting, for errands, and for exercise compared with those who lived in low SES areas. When the whole sample was examined, all environmental attributes were associated with walking behaviors (except for street density not being associated with walking for exercise). Associations of environmental attributes with walking behaviors were moderated by area-level SES only in walking for exercise. Walking for exercise was associated with higher population density, higher street density (marginally significant), and shorter distance to the nearest commercial destination only in high SES areas. Our findings showed that the associations of these environmental attributes and walking behaviors were largely consistent across different SES levels. Therefore, urban design interventions focusing on low SES areas may help to reduce socioeconomic disparities in walking.


Disc degeneration-related clinical phenotypes.
The phenotype, or observable trait of interest, is at the core of studies identifying associated genetic variants and their functional pathways, as well as diagnostics. Yet, despite remarkable technological developments in genotyping and progress in genetic research, relatively little attention has been paid to the equally important issue of phenotype. This is especially true for disc degeneration-related disorders, and the concept of degenerative disc disease, in particular, where there is little consensus or uniformity of definition. Greater attention and rigour are clearly needed in the development of disc degeneration-related clinical phenotypes if we are to see more rapid advancements in knowledge of this area. When selecting phenotypes, a basic decision is whether to focus directly on the complex clinical phenotype (e.g. the clinical syndrome of spinal stenosis), which is ultimately of interest, or an intermediate phenotype (e.g. dural sac cross-sectional area). While both have advantages, it cannot be assumed that associated gene variants will be similarly relevant to both. Among other considerations are factors influencing phenotype identification, comorbidities that are often present, and measurement issues. Genodisc, the European research consortium project on disc-related clinical pathologies has adopted a strategy that will allow for the careful characterisation and examination of both the complex clinical phenotypes of interest and their components.


Angular diagram of broadband emission of millimeter-sized water droplets exposed to gigawatt femtosecond laser pulses.
We report on the experiments on the interaction of gigawatt femtosecond laser pulses with suspended millimeter-sized water droplets. The transparent droplets experienced laser-induced breakdown and explosive boiling up and emitted a broadband radiation. This radiation covers the spectral range from 450 to 1100 nm and consists of the spectrum of laser pulse scattered and transformed by the droplet due to self-phase modulation and plasma emission produced in water during photoionization. The droplet emission spectrum showed remarkable broadening at all viewing angles and is maximal in the direction of the laser exit from the droplet. The enlargement of the droplet results in additional spectral spreading of the emitted radiation. The depth and amount of laser pulse spectral self-transformations upon propagation through the water droplet are simulated by means of numerical calculations.


Effects of high hydrostatic pressure, ultraviolet light-C, and far-infrared treatments on the digestibility, antioxidant and antihypertensive activity of α-casein.
Alpha-casein is the most important bioactive protein in processing technologies. This study investigated the digestibility, antioxidant and antihypertensive activities of α-casein when treated by high hydrostatic pressure (HPP), ultraviolet light-C (UV-C), and far-infrared radiation (FIR). The in vitro digestibility was modified after treatments, especially after 5min/200MPa HHP treatment. Ultra-performance liquid chromatography-tandem mass spectrometry analysis showed that one 5min/200MPa HHP treatment resulted in the highest yield of peptides. Based on the in vitro gastrointestinal digestion and antioxidant and antihypertensive activity assays, HHP increased the angiotensin converting enzyme inhibitory activity at different levels. The 15min UV-C treatment resulted in the highest antioxidant DPPH radical-scavenging activity, while the 15min UV-C and FIR treatments had higher angiotensin converting enzyme inhibitory and antioxidant activities than those of 5min treatments. This study revealed that HHP, UV-C and FIR treatments increased the antioxidant and antihypertensive activities of α-casein.


Microcavity array system for size-based enrichment of circulating tumor cells from the blood of patients with small-cell lung cancer.
In this study, we present a method for efficient enrichment of small-sized circulating tumor cells (CTCs) such as those found in the blood of small-cell lung cancer (SCLC) patients using a microcavity array (MCA) system. To enrich CTCs from whole blood, a microfabricated nickel filter with a rectangular MCA (10(4) cavities/filter) was integrated with a miniaturized device, allowing for the isolation of tumor cells based on differences in size and deformability between tumor and blood cells. The shape and porosity of the MCA were optimized to efficiently capture small tumor cells on the microcavities under low flow resistance conditions, while allowing other blood cells to effectively pass through. Under optimized conditions, approximately 80% of SCLC (NCI-H69 and NCI-H82) cells spiked in 1 mL of whole blood were successfully recovered. In clinical samples, CTCs were detectable in 16 of 16 SCLC patients. In addition, the number of leukocytes captured on the rectangular MCA was significantly lower than that on the circular MCA (p < 0.001), suggesting that the use of the rectangular MCA diminishes a considerable number of carryover leukocytes. Therefore, our system has potential as a tool for the detection of CTCs in small cell-type tumors and detailed molecular analyses of CTCs.


Cyborgs in the Everyday: Masculinity and Biosensing Prostate Cancer.
An in vivo biosensor is a technology in development that will assess the biological activity of cancers to individualise external beam radiotherapy. Inserting such technology into the human body creates cybernetic organisms; a cyborg that is a human-machine hybrid. There is a gap in knowledge relating to patient willingness to allow automated technology to be embedded and to become cyborg. There is little agreement around what makes a cyborg and less understanding of the variation in the cyborgisation process. Understanding the viewpoint of possible beneficiaries addresses such gaps. There are currently three versions of 'cyborg' in the literature (i) a critical feminist STS concept to destabilise power inherent in dualisms, (ii) an extreme version of the human/machine in science-fiction that emphasises the 'man' in human and (iii) a prediction of internal physiological adaptation required for future space exploration. Interview study findings with 12 men in remission from prostate cancer show a fourth version can be used to describe current and future sub-groups of the population; 'everyday cyborgs'. For the everyday cyborg the masculine cyborg status found in the fictionalised human-machine related to issues of control of the cancer. This was preferred to the felt stigmatisation of being a 'leaker and bleeder'. The willingness to become cyborg was matched with a having to get used to the everyday cyborg's technological adaptations and risks. It is crucial to explore the everyday cyborg's sometimes ambivalent viewpoint. The everyday cyborg thus adds the dimension of participant voice currently missing in existing cyborg literatures and imaginations.


Exploring the Neural Structures Underlying the Procedural Memory Network as Predictors of Language Ability in Children and Adolescents With Autism Spectrum Disorder and Attention Deficit Hyperactivity Disorder.
Introduction: There is significant overlap in the type of structural language impairments exhibited by children with autism spectrum disorder (ASD) and children with attention deficit hyperactivity disorder (ADHD). This similarity suggests that the cognitive impairment(s) contributing to the structural language deficits in ASD and ADHD may be shared. Previous studies have speculated that procedural memory deficits may be the shared cognitive impairment. The procedural deficit hypothesis (PDH) argues that language deficits can be explained by differences in the neural structures underlying the procedural memory network. This hypothesis is based on the premise that the neural structures comprising the procedural network support language learning. In this study, we aimed to test the PDH in children with ASD, ADHD, and typical development (TD). Methods: One hundred and sixty-three participants (ages 10-21): 91 with ASD, 26 with ADHD, and 46 with TD, completed standardized measures of cognitive and language ability as well as structural magnetic resonance imaging. We compared the structural language abilities, the neural structures underlying the procedural memory network, and the relationship between structural language and neural structure across diagnostic groups. Results: Our analyses revealed that while the structural language abilities differed across ASD, ADHD, and TD groups, the thickness, area, and volume of the structures supporting the procedural memory network were not significantly different between diagnostic groups. Also, several neural structures were associated with structural language abilities across diagnostic groups. Only two of these structures, the inferior frontal gyrus, and the left superior parietal gyrus, are known to be linked to the procedural memory network. Conclusions: The inferior frontal gyrus and the left superior parietal gyrus, have well-established roles in language learning independent of their role as part of the procedural memory system. Other structures such as the caudate and cerebellum, with critical roles in the procedural memory network, were not associated with structural language abilities across diagnostic groups. It is unclear whether the procedural memory network plays a fundamental role in language learning in ASD, ADHD, and TD.


The march of pluripotent stem cells in cardiovascular regenerative medicine.
Cardiovascular disease (CVD) continues to be the leading cause of global morbidity and mortality. Heart failure remains a major contributor to this mortality. Despite major therapeutic advances over the past decades, a better understanding of molecular and cellular mechanisms of CVD as well as improved therapeutic strategies for the management or treatment of heart failure are increasingly needed. Loss of myocardium is a major driver of heart failure. An attractive approach that appears to provide promising results in reducing cardiac degeneration is stem cell therapy (SCT). In this review, we describe different types of stem cells, including embryonic and adult stem cells, and we provide a detailed discussion of the properties of induced pluripotent stem cells (iPSCs). We also present and critically discuss the key methods used for converting somatic cells to pluripotent cells and iPSCs to cardiomyocytes (CMs), along with their advantages and limitations. Integrating and non-integrating reprogramming methods as well as characterization of iPSCs and iPSC-derived CMs are discussed. Furthermore, we critically present various methods of differentiating iPSCs to CMs. The value of iPSC-CMs in regenerative medicine as well as myocardial disease modeling and cardiac regeneration are emphasized.


TBS result is not affected by lumbar spine osteoarthritis.
The effect of lumbar osteoarthritis on bone density and trabecular bone score (TBS) was evaluated cross-sectionally and prospectively in postmenopausal women. Lumbar spine osteoarthritis was graded according to Kellgren and Lawrence grades. Lumbar osteoarthritis was found to increase lumbar spine bone density, but not TBS. Lumbar osteoarthritis overestimates lumbar bone density (areal bone mineral density (aBMD)). A new texture parameter, the TBS, has been proposed. Calculation of aBMD uses grey level value, while TBS uses grey level variation. Therefore, our hypothesis was that TBS is not influenced by lumbar spine osteoarthritis. Menopausal women participating in osteoporosis and ultrasound (OPUS) study were included. They had an aBMD measurement of the spine and hip at baseline and 6-year visit. TBS was calculated on lumbar spine dual-energy X-ray absorptiometry (DXA) scans in an automated manner. The presence of lumbar osteoarthritis was evaluated on baseline radiographs using Kellgren and Lawrence (K&L) classification. Grades range from 0 to 4. In our study, osteoarthritis was defined by at least K&L grade 2. This study included 1,254 menopausal women (66.7 ± 7.1 years). Among them, 727 attended the 6-year follow-up visit. Patients with lumbar osteoarthritis had an aBMD higher than those without lumbar osteoarthritis at the lumbar spine, but not at the hip. However, the aBMD significantly increased in all sites with the grade of K&L. In contrast, spine TBS was not different between patients with and without lumbar osteoarthritis (p = 0.70), and it was not correlated with K&L grade. Spine TBS and aBMD at all sites were negatively correlated with age (p < 0.0001). Body mass index was correlated positively with aBMD and negatively with spine TBS (p < 0.0001). The 6-year change of aBMD was significant in the hip and nonsignificant in the lumbar spine. That of TBS was significant, with a 3.3 % decrease (p < 0.0001), independent of K&L grade (p = 0.28). In postmenopausal women, lumbar osteoarthritis leads to an increase in lumbar spine aBMD. In contrast, spine TBS is not affected by lumbar osteoarthritis.


Negative frequency-dependent selection of sexually antagonistic alleles in Myodes glareolus.
Sexually antagonistic genetic variation, where optimal values of traits are sex-dependent, is known to slow the loss of genetic variance associated with directional selection on fitness-related traits. However, sexual antagonism alone is not sufficient to maintain variation indefinitely. Selection of rare forms within the sexes can help to conserve genotypic diversity. We combined theoretical models and a field experiment with Myodes glareolus to show that negative frequency-dependent selection on male dominance maintains variation in sexually antagonistic alleles. In our experiment, high-dominance male bank voles were found to have low-fecundity sisters, and vice versa. These results show that investigations of sexually antagonistic traits should take into account the effects of social interactions on the interplay between ecology and evolution, and that investigations of genetic variation should not be conducted solely under laboratory conditions.


Acute paretic syndrome in juvenile White Leghorn chickens resembles late stages of acute inflammatory demyelinating polyneuropathies in humans.
Sudden limb paresis is a common problem in White Leghorn flocks, affecting about 1% of the chicken population before achievement of sexual maturity. Previously, a similar clinical syndrome has been reported as being caused by inflammatory demyelination of peripheral nerve fibres. Here, we investigated in detail the immunopathology of this paretic syndrome and its possible resemblance to human neuropathies. Neurologically affected chickens and control animals from one single flock underwent clinical and neuropathological examination. Peripheral nervous system (PNS) alterations were characterised using standard morphological techniques, including nerve fibre teasing and transmission electron microscopy. Infiltrating cells were phenotyped immunohistologically and quantified by flow cytometry. The cytokine expression pattern was assessed by quantitative real-time PCR (qRT-PCR). These investigations were accomplished by MHC genotyping and a PCR screen for Marek's disease virus (MDV). Spontaneous paresis of White Leghorns is caused by cell-mediated, inflammatory demyelination affecting multiple cranial and spinal nerves and nerve roots with a proximodistal tapering. Clinical manifestation coincides with the employment of humoral immune mechanisms, enrolling plasma cell recruitment, deposition of myelin-bound IgG and antibody-dependent macrophageal myelin-stripping. Disease development was significantly linked to a 539 bp microsatellite in MHC locus LEI0258. An aetiological role for MDV was excluded. The paretic phase of avian inflammatory demyelinating polyradiculoneuritis immunobiologically resembles the late-acute disease stages of human acute inflammatory demyelinating polyneuropathy, and is characterised by a Th1-to-Th2 shift.


Improving pairwise comparison of protein sequences with domain co-occurrence.
Comparing and aligning protein sequences is an essential task in bioinformatics. More specifically, local alignment tools like BLAST are widely used for identifying conserved protein sub-sequences, which likely correspond to protein domains or functional motifs. However, to limit the number of false positives, these tools are used with stringent sequence-similarity thresholds and hence can miss several hits, especially for species that are phylogenetically distant from reference organisms. A solution to this problem is then to integrate additional contextual information to the procedure. Here, we propose to use domain co-occurrence to increase the sensitivity of pairwise sequence comparisons. Domain co-occurrence is a strong feature of proteins, since most protein domains tend to appear with a limited number of other domains on the same protein. We propose a method to take this information into account in a typical BLAST analysis and to construct new domain families on the basis of these results. We used Plasmodium falciparum as a case study to evaluate our method. The experimental findings showed an increase of 14% of the number of significant BLAST hits and an increase of 25% of the proteome area that can be covered with a domain. Our method identified 2240 new domains for which, in most cases, no model of the Pfam database could be linked. Moreover, our study of the quality of the new domains in terms of alignment and physicochemical properties show that they are close to that of standard Pfam domains. Source code of the proposed approach and supplementary data are available at: https://gite.lirmm.fr/menichelli/pairwise-comparison-with-cooccurrence.


Prognostic Impacts of Metastatic Site and Pain on Progression to Castrate Resistance and Mortality in Patients with Metastatic Prostate Cancer.
To investigate predictors of progression to castration-resistant prostate cancer (CRPC) and cancer-specific mortality (CSM) in patients with metastatic prostate cancer (mPCa). A retrospective analysis was performed on 440 consecutive treatment-naïve patients initially diagnosed with mPCa between August 2000 and June 2012. Patient age, body mass index (BMI), Gleason score, prostate-specific antigen (PSA), PSA nadir, American Joint Committee on Cancer stage, Visual Analogue Scale pain score, Eastern Cooperative Oncology Group performance score (ECOG PS), PSA response to hormone therapy, and metastatic sites were assessed. Cox-proportional hazards regression analyses were used to evaluate survivals and predictive variables of men with bone metastasis stratified according to the presence of pain, compared to men with visceral metastasis. Metastases were most often found in bone (75.4%), followed by lung (16.3%) and liver (8.3%) tissues. Bone metastasis, pain, and high BMI were associated with increased risks of progression to CRPC, and bone metastasis, pain, PSA nadir, and ECOG PS≥1 were significant predictors of CSM. During the median follow-up of 32.0 (interquartile range 14.7-55.9) months, patients with bone metastasis with pain and patients with both bone and visceral metastases showed the worst median progression to CRPC-free and cancer-specific survivals, followed by men with bone metastasis without pain. Patients with visceral metastasis had the best median survivals. Metastatic spread and pain patterns confer different prognosis in patients with mPCa. Bone may serve as a crucial microenvironment in the development of CRPC and disease progression.


Genetic diversity in oxytocin ligands and receptors in New World monkeys.
Oxytocin (OXT) is an important neurohypophyseal hormone that influences wide spectrum of reproductive and social processes. Eutherian mammals possess a highly conserved sequence of OXT (Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly). However, in this study, we sequenced the coding region for OXT in 22 species covering all New World monkeys (NWM) genera and clades, and characterize five OXT variants, including consensus mammalian Leu(8)-OXT, major variant Pro(8)-OXT, and three previously unreported variants: Ala(8)-OXT, Thr(8)-OXT, and Phe(2)-OXT. Pro(8)-OXT shows clear structural and physicochemical differences from Leu(8)-OXT. We report multiple predicted amino acid substitutions in the G protein-coupled OXT receptor (OXTR), especially in the critical N-terminus, which is crucial for OXT recognition and binding. Genera with same Pro(8)-OXT tend to cluster together on a phylogenetic tree based on OXTR sequence, and we demonstrate significant coevolution between OXT and OXTR. NWM species are characterized by high incidence of social monogamy, and we document an association between OXTR phylogeny and social monogamy. Our results demonstrate remarkable genetic diversity in the NWM OXT/OXTR system, which can provide a foundation for molecular, pharmacological, and behavioral studies of the role of OXT signaling in regulating complex social phenotypes.


Powder cocaine and crack use in the United States: an examination of risk for arrest and socioeconomic disparities in use.
In light of the current sentencing disparity (18:1) between crack and powder cocaine possession in the United States, we examined socioeconomic correlates of use of each, and relations between use and arrest, to determine who may be at highest risk for arrest and imprisonment. We conducted secondary data analyses on the National Survey on Drug Use and Health, 2009-2012. Data were analyzed for adults age ≥ 18 to determine associations between use and arrest. Socioeconomic correlates of lifetime and annual use of powder cocaine and of crack were delineated using multivariable logistic regression and correlates of frequency of recent use were examined using generalized negative binomial regression. Crack users were at higher risk than powder cocaine users for reporting a lifetime arrest or multiple recent arrests. Racial minorities were at low risk for powder cocaine use and Hispanics were at low risk for crack use. Blacks were at increased risk for lifetime and recent crack use, but not when controlling for other socioeconomic variables. However, blacks who did use either powder cocaine or crack tended to use at higher frequencies. Higher education and higher family income were negatively associated with crack use although these factors were sometimes risk factors for powder cocaine use. Crack users are at higher risk of arrest and tend to be of lower socioeconomic status compared to powder cocaine users. These findings can inform US Congress as they review bills (e.g., The Smarter Sentencing Act), which would help eliminate cocaine-related sentencing disparities.


Probing lasting cryoinjuries to oocyte-embryo transcriptome.
Clinical applications of oocytes cryopreservation include preservation of future fertility of young cancer patients, substitution of embryo freezing to avoid associated legal and ethical issues, and delaying childbearing years. While the outcome of oocyte cryopreservation has recently been improved, currently used vitrification method still suffer from increased biosafety risk and handling issues while slow freezing techniques yield overall low success. Understanding better the mechanism of cryopreservation-induced injuries may lead to development of more reliable and safe methods for oocyte cryopreservation. Using the mouse model, a microarray study was conducted on oocyte cryopreservation to identify cryoinjuries to transcriptionally active genome. To this end, metaphase II (MII) oocytes were subjected to standard slow freezing, and then analyzed at the four-cell stage after embryonic genome activation. Non-frozen four-cell embryos served as controls. Differentially expressed genes were identified and validated using RT-PCR. Embryos produced from the cryopreserved oocytes displayed 200 upregulated and 105 downregulated genes, associated with the regulation of mitochondrial function, protein ubiquitination and maintenance, cellular response to stress and oxidative states, fatty acid and lipid regulation/metabolism, and cell cycle maintenance. These findings reveal previously unrecognized effects of standard slow oocyte freezing on embryonic gene expression, which can be used to guide improvement of oocyte cryopreservation methods.


BagMOOV: A novel ensemble for heart disease prediction bootstrap aggregation with multi-objective optimized voting.
Conventional clinical decision support systems are based on individual classifiers or simple combination of these classifiers which tend to show moderate performance. This research paper presents a novel classifier ensemble framework based on enhanced bagging approach with multi-objective weighted voting scheme for prediction and analysis of heart disease. The proposed model overcomes the limitations of conventional performance by utilizing an ensemble of five heterogeneous classifiers: Naïve Bayes, linear regression, quadratic discriminant analysis, instance based learner and support vector machines. Five different datasets are used for experimentation, evaluation and validation. The datasets are obtained from publicly available data repositories. Effectiveness of the proposed ensemble is investigated by comparison of results with several classifiers. Prediction results of the proposed ensemble model are assessed by ten fold cross validation and ANOVA statistics. The experimental evaluation shows that the proposed framework deals with all type of attributes and achieved high diagnosis accuracy of 84.16 %, 93.29 % sensitivity, 96.70 % specificity, and 82.15 % f-measure. The f-ratio higher than f-critical and p value less than 0.05 for 95 % confidence interval indicate that the results are extremely statistically significant for most of the datasets.


Clinical and epidemiological features of coryneform skin infections at a tertiary hospital.
Skin infections caused by coryneform bacteria are common dermatological conditions. However, to the best of our knowledge, no studies are available on the clinical characteristics and epidemiological features of this group of disorders as one entity from India and abroad. To study the clinical and epidemiological features of coryneform skin infections. A total of 75 patients presenting with clinically distinctive lesions of pitted keratolysis, erythrasma and trichobacteriosis to our hospital were included in the study. Cases were interviewed with particular emphasis on epidemiological features and the various clinical findings were recorded. Investigations like Gram's stain, Wood's light examination, 10% KOH scrapings, were done in selected cases to ascertain the diagnosis. Pitted keratolysis was more common in the age group of 31-40 years (40%) with a male preponderance (76.7%), most commonly affecting pressure bearing areas of the soles with malodour (86.7%) and frequent contact with water (58.3%) constituting the most important presenting symptom and provocating factor respectively. Erythrasma affected both male and female patients equally and was more commonly detected in patients with a BMI > 23kg/m(2) (62.5%) and in diabetics (50%). All patients with trichobacteriosis presented with yellow coloured concretions in the axillae. Bromhidrosis (71.4%) and failure to regularly use an axillary deodorant (71.4%) were the most common presenting symptom and predisposing factor respectively. Coryneform skin infections are common dermatological conditions, though epidemiological data are fragmentary. Hyperhidrosis is a common predisposing factor to all three coryneform skin infections. Asymmetrical distribution of pits has been reported in our study. Diabetic status needs to be evaluated in all patients with erythrasma. Woods lamp examination forms an indispensible tool to diagnose erythrasma and trichobacteriosis.


Orientation Information in Encoding Facial Expressions for People With Central Vision Loss.
Patients with central vision loss face daily challenges on performing various visual tasks. Categorizing facial expressions is one of the essential daily activities. The knowledge of what visual information is crucial for facial expression categorization is important to the understanding of the functional performance of these patients. Here we asked how the performance for categorizing facial expressions depends on the spatial information along different orientations for patients with central vision loss. Eight observers with central vision loss and five age-matched normally sighted observers categorized face images into four expressions: angry, fearful, happy, and sad. An orientation filter (bandwidth = 23°) was applied to restrict the spatial information within the face images, with the center of the filter ranged from horizontal (0°) to 150° in steps of 30°. Face images without filtering were also tested. When the stimulus visibility was matched, observers with central vision loss categorized facial expressions just as well as their normally sighted counterparts, and showed similar confusion and bias patterns. For all four expressions, performance (normalized d'), uncorrelated with any of the observers' visual characteristics, peaked between -30° and 30° filter orientations and declined systematically as the filter orientation approached vertical (90°). Like normally sighted observers, observers with central vision loss also relied mainly on mouth and eye regions to categorize facial expressions. Similar to people with normal vision, people with central vision loss rely primarily on the spatial information around the horizontal orientation, in particular the regions around the mouth and eyes, for recognizing facial expressions.


Conformational sampling by NMR solution structures calculated with the program DIANA evaluated by comparison with long-time molecular dynamics calculations in explicit water.
The NMR solution structure of bovine pancreatic trypsin inhibitor (BPTI) obtained by distance geometry calculations with the program DIANA is compared with groups of conformers generated by molecular dynamics (MD) simulations in explicit water at ambient temperature and pressure. The MD simulations started from a single conformer and were free or restrained either by the experimental NOE distance restraints or by time-averaged restraints; the groups of conformers were collected either in 10 ps intervals during 200 ps periods of simulation, or in 50 ps intervals during a 1 ns period of simulation. Overall, these comparisons show that the standard protein structure determination protocol with the program DIANA provides a picture of the protein structure that is in agreement with MD simulations using "realistic" potential functions over a nanosecond timescale. For well-constrained molecular regions there is a trend in the free MD simulation of duration 1 ns that the sampling of the conformation space is slightly increased relative to the DIANA calculations. In contrast, for surface-exposed side-chains that are less extensively constrained by the NMR data, the DIANA conformers tend to sample larger regions of conformational space than conformers selected from any of the MD trajectories. Additional insights into the behavior of surface side-chains come from comparison of the MD runs of 200 ps or 1 ns duration. In this time range the sampling of conformation space by the protein surface depends strongly on the length of the simulation, which indicates that significant side-chain transitions occur on the nanosecond timescale and that much longer simulations will be needed to obtain statistically significant data on side-chain dynamics.


Adaptive immunity to rhinoviruses: sex and age matter.
Rhinoviruses (RV) are key triggers in acute asthma exacerbations. Previous studies suggest that men suffer from infectious diseases more frequently and with greater severity than women. Additionally, the immune response to most infections and vaccinations decreases with age. Most immune function studies do not account for such differences, therefore the aim of this study was to determine if the immune response to rhinovirus varies with sex or age. Blood mononuclear cells were isolated from 63 healthy individuals and grouped by sex and age (≤50 years old and ≥52 years old). Cells were cultured with rhinovirus 16 at a multiplicity of infection of 1. The chemokine IP-10 was measured at 24 h as an index of innate immunity while IFNγ and IL-13 were measured at 5 days as an index of adaptive immunity. Rhinovirus induced IFNγ and IL-13 was significantly higher in ≤50 year old women than in age matched men (p < 0.02 and p < 0.05) and ≥52 year old women (p < 0.02 and p > 0.005). There was no sex or age based difference in rhinovirus induced IP-10 expression. Both IFNγ and IL-13 were negatively correlated with age in women but not in men. This study suggests that pre-menopausal women have a stronger adaptive immune response to rhinovirus infection than men and older people, though the mechanisms responsible for these differences remain to be determined. Our findings highlight the importance of gender and age balance in clinical studies and in the development of new treatments and vaccines.


Antiestrogen therapy for breast cancer modifies the risk of subsequent cutaneous melanoma.
Increased risk of secondary melanoma after breast cancer has been reported. Several lines of evidence suggest that elevated estrogen levels may be implicated in melanoma etiology. Accordingly, use of antiestrogens should be associated with decreased risk of melanoma. We compared melanoma incidence among a cohort of breast cancer patients with and without antiestrogen therapy, with data from the Geneva Cancer Registry. The cohort consisted of 7,360 women diagnosed with breast cancer between 1980 and 2005. About 54% of these patients received antiestrogens. All women were followed until December 2008. We compared cutaneous melanoma incidence rates among patients with and without antiestrogens with those expected in the general population by age and period standardized incidence ratios (SIR). A total of 34 women developed a melanoma during the follow-up period. Compared with the general population, the risk of melanoma was higher for patients who did not receive antiestrogens (SIR: 1.60, 95% CI: 1.08-2.12, P = 0.02). On the contrary, the risk was close to 1 (SIR: 0.98, 95% CI: 0.40-1.56, P = 0.57) for patients who received antiestrogen therapy. This study suggests that antiestrogen therapy modifies the risk of melanoma after breast cancer. Although our results are in agreement with the hypothesis that estrogens could play a role in melanoma occurrence, they need to be replicated in a larger study with data on potential confounders. .


Surgical rescue of embolized amplatzer devices.
Transcatheter closure of atrial septal defect (ASD) and patent ductus arteriosus (PDA) with Amplatzer septal/duct occluder (ASO/ADO) is an established, safe, and efficient procedure with high success. However, device embolization remains a major complication requiring immediate intervention (either percutaneous or surgical) for retrieval and correction of the heart defect. The aim of this study is to share the experience of managing embolized ASO/ADO. Of the 284 cases of device closure performed from October 2002 to December 2010, four patients (1.4%) had device embolization requiring immediate surgical retrieval. Two adult female patients with secundum ASD had ASO device implanted. One embolized to the right ventricle and the other into the ascending aorta. An eight-month-old boy and a four-year-old girl with hypertensive PDA had device closure. Device embolization occurred into the descending aorta and right pulmonary artery, respectively. All four devices were retrieved and the defects closed successfully with a low morbidity and no mortality. Careful consideration should be given to surgical or transcatheter closure of a heart defect. Life-threatening complications although rare can occur. Our experience strongly suggests that these devices should only be inserted in facilities where cardiac surgical support is immediately available.


Cyclooxygenase-2 inhibition causes antiangiogenic effects on tumor endothelial and vascular progenitor cells.
Tumor angiogenesis is necessary for solid tumor progression and metastasis. Cyclooxygenase (COX)-2 is known to play an important role in cancer growth and invasion, and it activates the signaling pathways controlling cell proliferation, migration, apoptosis, and angiogenesis. COX-2 is reported to be expressed in many cancer cells. Several studies have reported successful treatment of cancer cells with COX-2 inhibitors (COX-2is). However, the effect of COX-2 inhibition on the tumor endothelium remains to be elucidated. Our study shows that COX-2 is expressed in the vasculature of surgically resected human tumors. To investigate the effects of COX-2 inhibition on the tumor endothelium in vitro, we isolated tumor endothelial cells (TECs) from human melanoma and oral carcinoma xenografts in mice, in which we confirmed that tumor growth was suppressed by inhibiting angiogenesis with the COX-2is NS398. COX-2 mRNA was upregulated in TECs compared to normal endothelial cells (NECs). Cell migration and proliferation were suppressed by NS398 in TECs but not in NECs. The effects of NS398 in vivo were consistent with the in vitro results. The number of CD133+ /vascular endothelial growth factor receptor-2+ cells in circulation was significantly suppressed by COX-2 inhibition. In addition, the number of progenitor marker-positive cells decreased in the tumor blood vessels after COX-2i treatment, which suggests that the homing of progenitor cells into the tumor was also blocked. We conclude that NS398 specifically targets both TECs and vascular progenitor cells without affecting NECs.


Targeted nanopore sequencing with Cas9-guided adapter ligation.
Despite recent improvements in sequencing methods, there remains a need for assays that provide high sequencing depth and comprehensive variant detection. Current methods1-4 are limited by the loss of native modifications, short read length, high input requirements, low yield or long protocols. In the present study, we describe nanopore Cas9-targeted sequencing (nCATS), an enrichment strategy that uses targeted cleavage of chromosomal DNA with Cas9 to ligate adapters for nanopore sequencing. We show that nCATS can simultaneously assess haplotype-resolved single-nucleotide variants, structural variations and CpG methylation. We apply nCATS to four cell lines, to a cell-line-derived xenograft, and to normal and paired tumor/normal primary human breast tissue. Median sequencing coverage was 675× using a MinION flow cell and 34× using the smaller Flongle flow cell. The nCATS sequencing requires only ~3 μg of genomic DNA and can target a large number of loci in a single reaction. The method will facilitate the use of long-read sequencing in research and in the clinic.


A STUDY OF THE RELATION OF PULMONARY AND BRONCHIAL CIRCULATION.
The most striking point brought out in this study is that as long as a definite pressure is maintained in either the pulmonary or bronchial circulations, the admixture of bloods is extremely limited. It is easily conceivable that more mixture occurs normally than under the conditions of the experiment, but there is no reason for considering this to be a large difference. If, however, in either system the pressure sinks to zero the possibility of supply by the other system becomes evident. It takes much longer for the mass injected through the bronchial arteries to penetrate to all parts of the lung than when the mass is injected through the pulmonary artery; but when accomplished, the injection reaches to all capillaries including those of the pleura, the only vessels remaining uninjected being the larger trunks of the pulmonary artery. On the other hand, the injection of the bronchial vessels by way of the pulmonary arteries is not complete with normal pressure, but occurs rapidly when a high pulmonary pressure is employed. It is therefore probable that either circulation can suffice for the simple nutritive demands of the lung if the other system is interfered with. It has been shown that embolism of the pulmonary artery, without other circulatory disturbance, does not lead to necrosis of the affected area of the lung, but it is probable that the preservation of circulation is not due to collateral bronchial circulation so much as to the free anastomosis and early division into capillaries of the pulmonary artery. In support of this statement is the fact that the appearance is not altered when the bronchials are ligated at their origin. The same ligation shows no subsequent interference with the nutrition of the bronchi up to a period of five weeks, demonstrating that the pulmonary circulation is sufficient to provide for the nutrition of the bronchi. If, however, as Virchow has shown, the pulmonary artery supplying an entire lobe be occluded, the bronchial circulation can and does suffice for the nutrition of the lobe. In the case of the occlusion of a branch of the pulmonary artery the pressure in the area interfered with does not sink to zero because of the collateral circulation in this area; whereas, if the main trunk is occluded no collateral supply is available, the pressure sinks to zero, and the bronchial artery becomes available as a source of blood supply. It must be remembered that the lung tissue, as a whole, has ready access to oxygen and this gas is the nutritive element acquired by the blood in the lungs. From these studies it would appear that the part of the lung tissue not in intimate contact with oxygen in the air is supplied by oxygenated blood of the bronchial arteries, and that the tissues through which the pulmonary blood circulates take up whatever organized nutriment they need from the pulmonary blood and possibly provide for their oxygen and carbon dioxide interchange (which must be very slight) either directly with the alveolar air, or by finding sufficient oxygen in the venous blood of the pulmonary artery. The studies of the injected specimens confirm Küttner's findings of a very rapid breaking up of the pulmonary artery into capillaries. In all the specimens studied it was found that although the pleural vessels can be injected by way of the bronchial arteries when there is zero pressure in the pulmonary arteries, yet when the two sets of vessels are injected simultaneously in the dog, the pleural vessels invariably derive their supply of injection mass from the pulmonary artery.


Importance of patient and processor variables in determining outcomes with cochlear implants.
Within-subjects comparisons of processing strategies for cochlear implants are reviewed. Compressed analog strategies were compared to interleaved pulses strategies in tests with one group of 8 subjects, and to continuous interleaved sampling strategies in tests with another group of 11 subjects. The tests included open-set recognition of words and sentences. The results show that, while different strategies may produce quite different outcomes across subjects, individual performances with one processing strategy are significantly correlated with those of alternative strategies. These findings emphasize the importance of patient variables in determining outcomes across a variety of prosthesis designs.


Deciphering the role of insertion sequences in the evolution of bacterial epidemic pathogens with panISa software.
Next-generation sequencing (NGS) is now widely used in microbiology to explore genome evolution and the structure of pathogen outbreaks. Bioinformatics pipelines readily detect single-nucleotide polymorphisms or short indels. However, bacterial genomes also evolve through the action of small transposable elements called insertion sequences (ISs), which are difficult to detect due to their short length and multiple repetitions throughout the genome. We designed panISa software for the ab initio detection of IS insertions in the genomes of prokaryotes. PanISa has been released as open source software (GPL3) available from https://github.com/bvalot/panISa. In this study, we assessed the utility of this software for evolutionary studies, by reanalysing five published datasets for outbreaks of human major pathogens in which ISs had not been specifically investigated. We reanalysed the raw data from each study, by aligning the reads against reference genomes and running panISa on the alignments. Each hit was automatically curated and IS-related events were validated on the basis of nucleotide sequence similarity, by comparison with the ISFinder database. In Acinetobacter baumannii, the panISa pipeline identified ISAba1 or ISAba125 upstream from the ampC gene, which encodes a cephalosporinase in all third-generation cephalosporin-resistant isolates. In the genomes of Vibrio cholerae isolates, we found that early Haitian isolates had the same ISs as Nepalese isolates, confirming the inferred history of the contamination of this island. In Enterococcus faecalis, panISa identified regions of high plasticity, including a pathogenicity island enriched in IS-related events. The overall distribution of ISs deduced with panISa was consistent with SNP-based phylogenic trees, for all species considered. The role of ISs in pathogen evolution has probably been underestimated due to difficulties detecting these transposable elements. We show here that panISa is a useful addition to the bioinformatics toolbox for analyses of the evolution of bacterial genomes. PanISa will facilitate explorations of the functional impact of ISs and improve our understanding of prokaryote evolution.


The impact of placental pathology discordance in multiple gestation pregnancies on bronchopulmonary dysplasia-associated pulmonary hypertension.
Bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH) may either be concordant or discordant between multiple gestation births. Abnormal placental development, particularly maternal vascular malperfusion, may account for discordance in BPD-PH through fetal programming mechanisms. Maternal vascular malperfusion is a placental histologic lesion associated with intrauterine growth restriction and BPD-PH. We conducted a retrospective longitudinal cohort study of infants born <29 weeks gestation with available placental histology at Prentice Women's Hospital in Chicago from 2005-2012. The primary outcome was discordant BPD-PH associated with placental maternal vascular malperfusion. We secondarily assessed whether the risk of BPD-PH and placental lesions was different among infants of multiple (compared to singleton) gestations. The cohort consisted of 135 multiple gestation infants and 355 singletons. In a separate cohort of 39 singletons and 35 multiples, associations between 12 cytokines and angiogenic growth factors in cord blood plasma for biomarker discordance, maternal vascular malperfusion, and bronchopulmonary dysplasia were explored. Among multiples, discordant maternal vascular malperfusion was not associated with BPD-PH (OR = 1.9 (0.52, 6.9); p = 0.33) in infants exposed to placental maternal vascular malperfusion. However, singleton infants were more likely to develop BPD-PH (compared to multiples) after adjusting for mode of delivery, chorioamnionitis, chronic hypertension, placental abruption, small-for-gestational age birth weight, and gestational age (aOR = 2.7 (1.2, 5.8); p = 0.038). Singletons were more likely to be small-for-gestational age (11% vs 4%, p = 0.025) and have placental lesions compared to their multiple-gestation counterparts (96% vs 81%, p < 0.001), principally severe maternal vascular malperfusion (17% vs 4%, p < 0.001) and chronic inflammation (32% vs 11%, p < 0.001). Increased risk of BPD-PH in singleton pregnancies <29 weeks gestation compared to multiples may be related to increased frequency of these histologic lesions. Placental pathology in singleton and multiple gestation pregnancies may serve as an early biomarker to predict BPD-PH.


Heterogeneities and consequences of Plasmodium species and hookworm coinfection: a population based study in Uganda.
Previous studies have suggested that helminth infection exacerbates malaria, but few existing epidemiological studies adequately control for infection heterogeneities and confounding factors. In this study, we investigate spatial and household heterogeneities, predictors, and consequences of Plasmodium species and hookworm coinfection in rural communities in Uganda. A cross-sectional study was conducted among 1770 individuals aged 0-88 years in 4 villages. We recorded demographic, socioeconomic, and microgeographic factors during household surveys. We determined malaria parasitemia and hemoglobin concentration and collected stool samples on 2 consecutive days. For data analysis, we used a hierarchical, spatially explicit Bayesian framework. Prevalence of Plasmodium-hookworm coinfection was 15.5% overall and highest among school-aged children. We found strong evidence of spatial and household clustering of coinfection and an enduring positive association between Plasmodium-species and hookworm infection among preschool-aged children (odds ratio [OR], 2.36; 95% Bayesian credible interval [BCI], 1.26-4.30) and adults (OR, 2.09; 95% BCI, 1.35-3.16) but not among school-aged children. Coinfection was associated with lower hemoglobin level only among school-aged children. Plasmodium-hookworm coinfection exhibits marked age dependency and significant spatial and household heterogeneity, and among preschool-aged children and adults, occurs more than would be expected by chance. Such heterogeneities provide insight into factors underlying observed patterns and the design of integrated control strategies.


Combining Salmonella Dublin genome information and contact-tracing to substantiate a new approach for improved detection of infectious transmission routes in cattle populations.
This study presents a new method for detection of between-herd livestock movements to facilitate disease tracing and more accurately describe network behaviour of relevance for spread of infectious diseases, including within-livestock business risk-carrying contacts that are not necessarily recorded anywhere. The study introduces and substantiates the concept of grouping livestock herds into business-units based on ownership and location in the tracing analysis of animal movement-based contact networks. To test the utility of this approach, whole core genome sequencing of 196 Salmonella Dublin isolates stored from previous surveillance and project activities was combined with information on cattle movements recorded in the Danish Cattle Database between 1997 and 2017. The aim was to investigate alternative explanations for S. Dublin circulation in groups of herds connected by ownership, but without complete records of livestock movements. The EpiContactTrace R-package was used to trace the contact networks between businesses and compare the network characteristics of businesses sharing strains of S. Dublin with different levels of genetic relatedness. The ownership-only definition proved to be an unreliable grouping approach for large businesses, which could have internal distances larger than 250 km and therefore do not represent useful epidemiological units. Therefore, the grouping was refined using spatial analysis. More than 90% of final business units formed were composed of one single cattle property, whereas multi-property businesses could reach up to eight properties in a given year, with up to 15 cattle herds having been part of the same business through the study period. Results showed markedly higher probabilities of introduction of infectious animals between proposed businesses from which the same clone of S. Dublin had been isolated, when compared to businesses with non-related strains, thus substantiating the business-unit as an important epidemiological feature to consider in contact network analysis and tracing of infection routes. However, this approach may overestimate real-life contacts between cattle properties and putatively overestimate the degree of risk-contacts within each business, since it is based solely on information about property ownership and location. This does not consider administrative and individual farmers behaviours that essentially keep two properties separated. Despite this, we conclude that defining epidemiological units based on businesses is a promising approach for future disease tracing tasks.


Reprint of: Review of bioactive glass: From Hench to hybrids.
Bioactive glasses are reported to be able to stimulate more bone regeneration than other bioactive ceramics but they lag behind other bioactive ceramics in terms of commercial success. Bioactive glass has not yet reached its potential but research activity is growing. This paper reviews the current state of the art, starting with current products and moving onto recent developments. Larry Hench's 45S5 Bioglass® was the first artificial material that was found to form a chemical bond with bone, launching the field of bioactive ceramics. In vivo studies have shown that bioactive glasses bond with bone more rapidly than other bioceramics, and in vitro studies indicate that their osteogenic properties are due to their dissolution products stimulating osteoprogenitor cells at the genetic level. However, calcium phosphates such as tricalcium phosphate and synthetic hydroxyapatite are more widely used in the clinic. Some of the reasons are commercial, but others are due to the scientific limitations of the original Bioglass 45S5. An example is that it is difficult to produce porous bioactive glass templates (scaffolds) for bone regeneration from Bioglass 45S5 because it crystallizes during sintering. Recently, this has been overcome by understanding how the glass composition can be tailored to prevent crystallization. The sintering problems can also be avoided by synthesizing sol-gel glass, where the silica network is assembled at room temperature. Process developments in foaming, solid freeform fabrication and nanofibre spinning have now allowed the production of porous bioactive glass scaffolds from both melt- and sol-gel-derived glasses. An ideal scaffold for bone regeneration would share load with bone. Bioceramics cannot do this when the bone defect is subjected to cyclic loads, as they are brittle. To overcome this, bioactive glass polymer hybrids are being synthesized that have the potential to be tough, with congruent degradation of the bioactive inorganic and the polymer components. Key to this is creating nanoscale interpenetrating networks, the organic and inorganic components of which have covalent coupling between them, which involves careful control of the chemistry of the sol-gel process. Bioactive nanoparticles can also now be synthesized and their fate tracked as they are internalized in cells. This paper reviews the main developments in the field of bioactive glass and its variants, covering the importance of control of hierarchical structure, synthesis, processing and cellular response in the quest for new regenerative synthetic bone grafts. The paper takes the reader from Hench's Bioglass 45S5 to new hybrid materials that have tailorable mechanical properties and degradation rates.


Phylogenesys and homology modeling in Zika virus epidemic: food for thought.
Zika virus (ZIKV) is an emerging Flavivirus that have recently caused an outbreak in Brazil and rapid spread in several countries. In this study, the consequences of ZIKV evolution on protein recognition by the host immune system have been analyzed. Evolutionary analysis was combined with homology modeling and T-B cells epitope predictions. Two separate clades, the African one with the Uganda sequence, as the most probable ancestor, and the second one containing all the most recent sequences from the equatorial belt were identified. Brazilian strains clustered all together and closely related to the French Polynesia isolates. A strong presence of a negatively selected site in the envelope gene (Env) protein was evidenced, suggesting a probable purging of deleterious polymorphisms in functionally important genes. Our results show relative conservancy of ZIKV sequences when envelope and other non-structural proteins (NS3 and NS5) are analyzed by homology modeling. However, some regions within the consensus sequence of NS5 protein and to a lesser extent in the envelope protein, show localized high mutation frequency corresponding to a considerable alteration in protein stability. In terms of viral immune escape, envelope protein is under a higher selective pressure than NS5 and NS3 proteins for HLA class I and II molecules. Moreover, envelope mutations that are not strictly related to T-cell immune responses are mostly located on the surface of the protein in putative B-cell epitopes, suggesting an important contribution of B cells in the immune response as well.


Incremental patterns in the amount of informal and formal care among non-demented and demented elderly persons: results from a 3-year follow-up population-based study.
Elderly care includes complex interactions between formal services, informal care, morbidity and disabilities. Studies of the incremental effects of formal and informal care are rare and thus the objective was to describe the longitudinal patterns in formal and informal care given to non-demented and demented persons living in a rural area in Sweden. Transitions in the Kungsholmen-Nordanstig Project (n=919) was followed up 3 years later (n=579), presented as different combinations of informal and formal care, institutionalization and mortality. Number of hours spent on care was examined by the Resource Utilization in Dementia instrument (RUD). Bootstrapped descriptive statistics and regression models were applied. The overall mortality during follow-up was 34%, and 15% had been institutionalized. Of those who lived at home, those receiving only formal care had been institutionalized to the greatest extent (29%; p<0.05). In terms of hours, informal care decreased amongst demented. The ratio between demented and non-demented was greater at baseline, both regarding informal care (10:1 and 3:1, respectively) and formal care (5:1 and 4:1, respectively). People with mild cognitive decline and no home support at baseline had a great risk of being receiver of care (formal or informal) or dead at follow-up. The amount of informal care was lower for demented persons still living at home at follow-up than at baseline, probably due to selection effects (institutionalization and mortality). Mild cognitive decline of non-users of care at baseline was strongly associated with receiving care or being dead at follow-up.


AAAPT Diagnostic Criteria for Acute Low Back Pain with and Without Lower Extremity Pain.
Low back pain is one of the most common reasons for which people visit their doctor. Between 12% and 15% of the US population seek care for spine pain each year, with associated costs exceeding $200 billion. Up to 80% of adults will experience acute low back pain at some point in their lives. This staggering prevalence supports the need for increased research to support tailored clinical care of low back pain. This work proposes a multidimensional conceptual taxonomy. A multidisciplinary task force of the ACTTION-APS-AAPM Pain Taxonomy (AAAPT) with clinical and research expertise performed a focused review and analysis, applying the AAAPT five-dimensional framework to acute low back pain. Application of the AAAPT framework yielded the following: 1) Core Criteria: location, timing, and severity of acute low back pain were defined; 2) Common Features: character and expected trajectories were established in relevant subgroups, and common pain assessment tools were identified; 3) Modulating Factors: biological, psychological, and social factors that modulate interindividual variability were delineated; 4) Impact/Functional Consequences: domains of impact were outlined and defined; 5) Neurobiological Mechanisms: putative mechanisms were specified including nerve injury, inflammation, peripheral and central sensitization, and affective and social processing of acute low back pain. The goal of applying the AAAPT taxonomy to acute low back pain is to improve its assessment through a defined evidence and consensus-driven structure. The criteria proposed will enable more rigorous meta-analyses and promote more generalizable studies of interindividual variation in acute low back pain and its potential underlying mechanisms.


The association of BRCA1 and BRCA2 mutations with prostate cancer risk, frequency, and mortality: A meta-analysis.
A prior meta-analysis found no association between BRCA1 mutation and prostate cancer (PCa). Subsequent BRCA2 mutation studies have shown an association with PCa risk and mortality. We conducted a meta-analysis of overall BRCA mutation carriers and in subgroups to (1) estimate PCa risk in BRCA mutation carriers, (2) evaluate the frequency of BRCA mutation carriers in patients with PCa, and (3) compare cancer-specific survival (CSS) and overall survival (OS) among BRCA mutation carriers and noncarriers. We searched the PubMed/MEDLINE, Embase, and Cochrane databases. Unadjusted odds ratio (OR), percentage (%), and hazard ratio (HR) were used to calculate pooled estimates for PCa risk, frequency, and survival, respectively. Subgroup analyses by mutation type ( BRCA1 or BRCA2) were conducted for the three objectives. Further subgroup analyses by study design (age-sex-adjusted or crude), ascertainment method (ascertained or inferred genotyping), population (Ashkenazi Jewish or general population), and survival outcomes (CSS or OS) were conducted. The associations were evaluated using random-effects models, in two-sided statistical tests. A total of 8 cohort, 7 case-control, 4 case-series, 28 frequency, and 11 survival studies were included. Being a BRCA mutation carrier ( BRCA1 and/or BRCA2) was associated with a significant increase in PCa risk (OR = 1.90, 95% CI = 1.58-2.29), with BRCA2 mutation being associated with a greater risk of PCa (OR = 2.64, 95% CI = 2.03-3.47) than BRCA1 (OR = 1.35, 95% CI = 1.03-1.76). The frequency of BRCA1 and BRCA2 carriers in patients with PCa was 0.9% and 2.2%, respectively. OS (HR = 2.21, 95% CI = 1.64-2.30) and CSS (HR = 2.63, 95% CI = 2.00-3.45) were significantly worse among BRCA2 carriers compared to noncarriers, whereas OS (HR = 0.47, 95% CI = 0.11-1.99) and CSS (HR = 1.07, 95% CI = 0.38-2.96) were statistically not significant when comparing BRCA1 carriers and noncarriers. There is a 1.90-fold greater risk of PCa in overall BRCA mutation carriers. This elevated PCa risk is attributable mainly to a 2.64-fold greater risk of PCa in BRCA2 carriers compared to a moderate 1.35-fold greater risk in BRCA1 carriers. The frequency of BRCA2 mutations was higher than BRCA1 mutations among patients with PCa. BRCA2 but not BRCA1 mutations were associated with higher PCa mortality. The BRCA mutation may be a clinical factor to stratify high-risk patients and guide clinical strategies for more effective treatments for patients with PCa.


Antigenic structure of polioviruses of serotypes 1, 2 and 3.
The antigenic sites recognized by monoclonal antibodies with neutralizing activity for the Sabin vaccine strains of poliovirus of serotypes 1, 2 and 3 have been studied by the isolation and characterization of mutants resistant to neutralization by antibody. Three distinct sites have been identified which are designated site 1, site 2 and site 3. Site 1 includes a region of 12 amino acids of VP1, from residues 89 to 100, and a corresponding region of VP1 has been identified as an antigenic site for poliovirus 2. This site was strongly immunodominant in type 2 and type 3 but was not detected for poliovirus 1. Site 2 is a complex site including residues 220 to 222 from VP1 (site 2a) with residues including 169 and 170 and others of VP2 (site 2b). Both site 2a and site 2b have been detected in type 1 poliovirus, while as yet only site 2b has been detected in type 3 poliovirus. Site 3 is a complex site including residues 286 to 290 from VP1 (site 3a) with residues including 58 and 59 and others of VP3 (site 3b). Both sites 3a and 3b have been detected in type 3 poliovirus, while as yet only site 3b has been detected in type 1 poliovirus.


Comparing Prescribing and Dispensing Data of the PCORnet Common Data Model Within PCORnet Antibiotics and Childhood Growth Study.
Researchers often use prescribing data from electronic health records (EHR) or dispensing data from medication or medical claims to determine medication utilization. However, neither source has complete information on medication use. We compared antibiotic prescribing and dispensing records for 200,395 patients in the National Patient-Centered Clinical Research Network (PCORnet) Antibiotics and Childhood Growth Study. We stratified analyses by delivery system type [closed integrated (cIDS) and non-cIDS]; 90.5 percent and 39.4 percent of prescribing records had matching dispensing records, and 92.7 percent and 64.0 percent of dispensing records had matching prescribing records at cIDS and non-cIDS, respectively. Most of the dispensings without a matching prescription did not have same-day encounters in the EHR, suggesting they were medications given outside the institution providing data, such as those from urgent care or retail clinics. The sensitivity of prescriptions in the EHR, using dispensings as a gold standard, was 99.1 percent and 89.9 percent for cIDS and non-cIDS, respectively. Only 0.7 percent and 6.1 percent of patients at cIDS and non-cIDS, respectively, were classified as false-negative, i.e. entirely unexposed to antibiotics when they in fact had dispensings. These patients were more likely to have a complex chronic condition or asthma. Overall, prescription records worked well to identify exposure to antibiotics. EHR data, such as the data available in PCORnet, is a unique and vital resource for clinical research. Closing data gaps by understanding why prescriptions may not be captured can improve this type of data, making it more robust for observational research.


EphA2 as a promoter of melanoma tumorigenicity.
The greatest health threat from malignant melanoma is death due to metastatic disease. Consequently, the identification of markers predictive of metastatic disease is essential for identifying new therapeutic targets. EphA2, a protein tyrosine kinase receptor commonly expressed in epithelial cells, has been found to be overexpressed and constitutively active in melanoma tumor cells having a metastatic phenotype as characterized by increased invasion, proliferation and vasculogenic mimicry (VM). Based on this observation, we hypothesized that increased expression of EphA2 by melanoma tumor cells could promote these characteristics of a metastatic phenotype in addition to promoting tumorigenicity as a whole. We analyzed a panel of human melanoma tumor cell lines derived from patient tissues classified as primary (either radial growth phase or vertical growth phase) and/or metastatic for the expression of EphA2 and found a correlation between increased EphA2 expression and metastatic potential. Experiments using the most metastatic of the human melanoma cell lines demonstrated that downregulation of EphA2 results in a significant decrease in invasion, proliferation, clonogenicity and VM in vitro, in addition to suppressed tumorigenicity in an orthotopic mouse model. Lastly, utilization of a human phospho-kinase array revealed increased phosphorylation of several different protein kinases involved in mediating various aspects of cellular proliferation. To the best of our knowledge these results provide the first direct in vivo evidence demonstrating a role for EphA2 in promoting melanoma tumorigenicity and suggest EphA2 as a significant molecular target for the therapeutic intervention of malignant melanoma.


Interaction force in a vertical dust chain inside a glass box.
Small number dust particle clusters can be used as probes for plasma diagnostics. The number of dust particles as well as cluster size and shape can be easily controlled employing a glass box placed within a Gaseous Electronics Conference (GEC) rf reference chamber to provide confinement of the dust. The plasma parameters inside this box and within the larger plasma chamber have not yet been adequately defined. Adjusting the rf power alters the plasma conditions causing structural changes of the cluster. This effect can be used to probe the relationship between the rf power and other plasma parameters. This experiment employs the sloshing and breathing modes of small cluster oscillations to examine the relationship between system rf power and the particle charge and plasma screening length inside the glass box. The experimental results provided indicate that both the screening length and dust charge decrease as rf power inside the box increases. The decrease in dust charge as power increases may indicate that ion trapping plays a significant role in the sheath.


Is Heart Rate Variability Related to Season of Birth?
Season of birth (SOB) has been found to be related to cardiovascular mortality, but the mechanisms are unclear. It is suggested that birth in winter is a protective factor for the circulatory system, and this should be able to be observed using heart rate variability (HRV) measurements. The phenomenon may have a sex difference and is likely to be modulated by climatic factors. This study focused on this problem and investigates healthy school-age children to minimize confounding factors. Birth in winter is protective to cardiovascular system via autonomic modulation. There is a gender difference in the relationship between SOB and autonomic activity. Climatic factors are the cause of SOB effects on autonomic system. A total of 381 healthy school-age children were recruited for this study. Their HRV profiles were measured once and climatic information related to their month of birth was gathered. The HRV profiles of the 2 sexes and 4 seasons of birth were compared. Correlation and regression analysis were performed to clarify the relationship between climatic factors and the HRV results. Boys born in winter have higher high-frequency power (HF) but a lower ratio of low-frequency power to high-frequency power (LF/HF) than do males born in other seasons. This result is not found for girls. Age and the temperature of the SOB are predictive factors for HF among boys. The humidity of SOB is a predictive factor for normalized low-frequency power (LF%) and LF/HF among girls. Season of birth is related to both parasympathetic and sympathetic activity among school-age children, especially boys. Temperature and humidity are potential causes of this SOB phenomenon.


Coping styles and sex differences in depressive symptoms and delinquent behavior.
Building on research that links gender to differences in well-being and differences in stress exposure and vulnerability, the current study examines how coping styles are gendered in ways that may contribute to sex differences in depressive symptoms and delinquent behavior. The study disaggregates stress measures to reflect gender differences in the experience of stress, examining whether avoidant, approach, and action coping condition the relationship between stress and well-being. Regression analyses were conducted using data from the National Longitudinal Study of Adolescent Health. Results revealed sex differences and similarities. The interaction of avoidant coping and stress helped explain why girls had more depressive symptoms than boys, action coping increased delinquent behavior for girls, while approach coping decreased delinquent behavior for boys and girls. Assisting adolescents in developing coping styles that discourage avoiding problems or taking quick action, but that encourage problem-solving, can improve well-being, regardless of sex.


Geometrid outbreak waves travel across Europe.
We show that the population ecology of the 9- to 10-year cyclic, broadleaf-defoliating winter moth (Operophtera brumata) and other early-season geometrids cannot be fully understood on a local scale unless population behaviour is known on a European scale. Qualitative and quantitative data on O. brumata outbreaks were obtained from published sources and previously unpublished material provided by authors of this article. Data cover six decades from the 1950s to the first decade of twenty-first century and most European countries, giving new information fundamental for the understanding of the population ecology of O. brumata. Analyses on epicentral, regional and continental scales show that in each decade, a wave of O. brumata outbreaks travelled across Europe. On average, the waves moved unidirectionally ESE-WNW, that is, toward the Scandes and the Atlantic. When one wave reached the Atlantic coast after 9-10 years, the next one started in East Europe to travel the same c. 3000 km distance. The average wave speed and wavelength was 330 km year(-1) and 3135 km, respectively, the high speed being incongruous with sedentary geometrid populations. A mapping of the wave of the 1990s revealed that this wave travelled in a straight E-W direction. It therefore passed the Scandes diagonally first in the north on its way westward. Within the frame of the Scandes, this caused the illusion that the wave moved N-S. In analogy, outbreaks described previously as moving S-N or occurring contemporaneously along the Scandes were probably the result of continental-scale waves meeting the Scandes obliquely from the south or in parallel. In the steppe zone of eastern-most and south-east Europe, outbreaks of the winter moth did not participate in the waves. Here, broadleaved stands are small and widely separated. This makes the zone hostile to short-distance dispersal between O. brumata subpopulations and prevents synchronization within meta-populations. We hypothesize that hostile boundary models, involving reciprocal host-herbivore-enemy reactions at the transition between the steppe and the broadleaved forest zones, offer the best explanation to the origin of outbreak waves. These results have theoretical and practical implications and indicate that multidisciplinary, continentally coordinated studies are essential for an understanding of the spatio-temporal behaviour of cyclic animal populations.


Genetic analysis in cardiovascular disease: a clinical perspective.
Many forms of cardiovascular disease (CVD) demonstrate heritability and thus a genetic contribution is likely. This is most evident when considering the "simple" Mendelian traits such as hypertrophic cardiomyopathy. However, family history also influences our assessment of patients with complex traits such as coronary artery disease, hypertension, and common forms of hypercholesterolemia, as observed in clinical practice. Recent research has led to advances in our understanding of the genetic basis of both the simple and complex forms of CVD. This review presents the current state of knowledge regarding major gene disorders, as well as more common, complex forms of CVD such as coronary artery disease. It discusses the fundamental approaches being used to identify the genetic basis of the various disease states, as well as the practical implications of the discoveries to clinicians. It also focuses on our need to assess the extent by which genetic analysis can alter our calculation of an individual's risk of disease, and our ability to successfully target treatment that will modify this process.


Worksite influences on obesogenic behaviors in low-wage workers in St Louis, Missouri, 2013-2014.
More than one-third of US adults are obese. Workplace programs to reduce obesity and improve overall health are not available or accessible to all workers, particularly low-wage workers among whom obesity is more prevalent. The goal of the study was to identify modifiable workplace factors and behaviors associated with diet and exercise to inform future workplace interventions to improve health. We distributed paper and online surveys to 2 groups of low-wage workers, hospital workers and retail sales workers, at the worksites. The surveys assessed obesity, obesogenic behaviors, workplace factors, and worker participation in workplace health programs (WHPs). Descriptive and regression analyses were conducted to examine workplace factors associated with obesogenic behaviors. A total of 529 surveys were completed (219 hospital workers and 310 retail workers). More than 40% of workers were obese and 27% were overweight. In general, workers had poor diets (frequent consumption of sugary and high-fat foods) and engaged in little physical activity (only 30.9% met recommended physical activity guidelines). Access to and participation in workplace health programs varied greatly between hospital and retail sales workers. We identified several modifiable workplace factors, such as food source and work schedule, that were associated with diet, exercise, or participation in workplace health programs. This study illustrates the high prevalence of obesity and obesogenic behaviors workers in 2 low-wage groups. The differences between work groups indicated that each group had unique facilitators and barriers to healthy eating and exercise. An understanding of how socioeconomic, demographic, and work-related factors influence health will help to identify high-risk populations for intervention and to design interventions tailored and relevant to the target audiences.


Japanese-US common-arm analysis of paclitaxel plus carboplatin in advanced non-small-cell lung cancer: a model for assessing population-related pharmacogenomics.
PURPOSE To explore whether population-related pharmacogenomics contribute to differences in patient outcomes between clinical trials performed in Japan and the United States, given similar study designs, eligibility criteria, staging, and treatment regimens. METHODS We prospectively designed and conducted three phase III trials (Four-Arm Cooperative Study, LC00-03, and S0003) in advanced-stage, non-small-cell lung cancer, each with a common arm of paclitaxel plus carboplatin. Genomic DNA was collected from patients in LC00-03 and S0003 who received paclitaxel (225 mg/m(2)) and carboplatin (area under the concentration-time curve, 6). Genotypic variants of CYP3A4, CYP3A5, CYP2C8, NR1I2-206, ABCB1, ERCC1, and ERCC2 were analyzed by pyrosequencing or by PCR restriction fragment length polymorphism. Results were assessed by Cox model for survival and by logistic regression for response and toxicity. Results Clinical results were similar in the two Japanese trials, and were significantly different from the US trial, for survival, neutropenia, febrile neutropenia, and anemia. There was a significant difference between Japanese and US patients in genotypic distribution for CYP3A4*1B (P = .01), CYP3A5*3C (P = .03), ERCC1 118 (P < .0001), ERCC2 K751Q (P < .001), and CYP2C8 R139K (P = .01). Genotypic associations were observed between CYP3A4*1B for progression-free survival (hazard ratio [HR], 0.36; 95% CI, 0.14 to 0.94; P = .04) and ERCC2 K751Q for response (HR, 0.33; 95% CI, 0.13 to 0.83; P = .02). For grade 4 neutropenia, the HR for ABCB1 3425C-->T was 1.84 (95% CI, 0.77 to 4.48; P = .19). CONCLUSION Differences in allelic distribution for genes involved in paclitaxel disposition or DNA repair were observed between Japanese and US patients. In an exploratory analysis, genotype-related associations with patient outcomes were observed for CYP3A4*1B and ERCC2 K751Q. This common-arm approach facilitates the prospective study of population-related pharmacogenomics in which ethnic differences in antineoplastic drug disposition are anticipated.


Electromechanically driven variable-focus lens based on transparent dielectric elastomer.
Dielectric elastomers with low elastic stiffness and high dielectric constant are smart materials that produce large strains (up to 300%) and belong to the group of electroactive polymers. Dielectric elastomer actuators are made from films of dielectric elastomers coated on both sides with compliant electrode material. Poly(3,4-ethylenedioxythiophene) (PEDOT), which is known as a transparent conducting polymer, has been widely used as an interfacial layer or polymer electrode in polymer electronic devices. In this study, we propose the transparent dielectric elastomer as a material of actuator driving variable-focus lens system using PEDOT as a transparent electrode. The variable-focus lens module has light transmittance up to 70% and maximum displacement up to 450. When voltage is applied to the fabricated lens module, optical focal length is changed. We anticipate our research to be a starting point for new model of variable-focus lens system. This system could find applications in portable devices, such as digital cameras, camcorder, and cell phones.


Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific association for the study of the liver (APASL): an update.
The first consensus report of the working party of the Asian Pacific Association for the Study of the Liver (APASL) set up in 2004 on acute-on-chronic liver failure (ACLF) was published in 2009. With international groups volunteering to join, the "APASL ACLF Research Consortium (AARC)" was formed in 2012, which continued to collect prospective ACLF patient data. Based on the prospective data analysis of nearly 1400 patients, the AARC consensus was published in 2014. In the past nearly four-and-a-half years, the AARC database has been enriched to about 5200 cases by major hepatology centers across Asia. The data published during the interim period were carefully analyzed and areas of contention and new developments in the field of ACLF were prioritized in a systematic manner. The AARC database was also approached for answering some of the issues where published data were limited, such as liver failure grading, its impact on the 'Golden Therapeutic Window', extrahepatic organ dysfunction and failure, development of sepsis, distinctive features of acute decompensation from ACLF and pediatric ACLF and the issues were analyzed. These initiatives concluded in a two-day meeting in October 2018 at New Delhi with finalization of the new AARC consensus. Only those statements, which were based on evidence using the Grade System and were unanimously recommended, were accepted. Finalized statements were again circulated to all the experts and subsequently presented at the AARC investigators meeting at the AASLD in November 2018. The suggestions from the experts were used to revise and finalize the consensus. After detailed deliberations and data analysis, the original definition of ACLF was found to withstand the test of time and be able to identify a homogenous group of patients presenting with liver failure. New management options including the algorithms for the management of coagulation disorders, renal replacement therapy, sepsis, variceal bleed, antivirals and criteria for liver transplantation for ACLF patients were proposed. The final consensus statements along with the relevant background information and areas requiring future studies are presented here.


Disappearing scales in carps: re-visiting Kirpichnikov's model on the genetics of scale pattern formation.
The body of most fishes is fully covered by scales that typically form tight, partially overlapping rows. While some of the genes controlling the formation and growth of fish scales have been studied, very little is known about the genetic mechanisms regulating scale pattern formation. Although the existence of two genes with two pairs of alleles (S&s and N&n) regulating scale coverage in cyprinids has been predicted by Kirpichnikov and colleagues nearly eighty years ago, their identity was unknown until recently. In 2009, the 'S' gene was found to be a paralog of fibroblast growth factor receptor 1, fgfr1a1, while the second gene called 'N' has not yet been identified. We re-visited the original model of Kirpichnikov that proposed four major scale pattern types and observed a high degree of variation within the so-called scattered phenotype due to which this group was divided into two sub-types: classical mirror and irregular. We also analyzed the survival rates of offspring groups and found a distinct difference between Asian and European crosses. Whereas nude × nude crosses involving at least one parent of Asian origin or hybrid with Asian parent(s) showed the 25% early lethality predicted by Kirpichnikov (due to the lethality of the NN genotype), those with two Hungarian nude parents did not. We further extended Kirpichnikov's work by correlating changes in phenotype (scale-pattern) to the deformations of fins and losses of pharyngeal teeth. We observed phenotypic changes which were not restricted to nudes, as described by Kirpichnikov, but were also present in mirrors (and presumably in linears as well; not analyzed in detail here). We propose that the gradation of phenotypes observed within the scattered group is caused by a gradually decreasing level of signaling (a dose-dependent effect) probably due to a concerted action of multiple pathways involved in scale formation.


Topical application of a sandal wood oil and turmeric based cream prevents radiodermatitis in head and neck cancer patients undergoing external beam radiotherapy: a pilot study.
The study objective was to assess the effectiveness of a turmeric- and sandal wood oil-containing cream [Vicco(®) turmeric cream (VTC); Vicco Laboratories, Parel, India] on radiodermatitis in patients with head and neck cancer undergoing radiotherapy. A total of 50 patients with head and neck cancer requiring >60 Gy of curative radiotherapy/chemoradiotherapy were enrolled in the study. The volunteers were randomly divided into two groups of 25 patients. Group 1 was assigned to a topical application of Johnson's(®) baby oil (Johnson & Johnson Ltd, Baddi, India) and Group 2 for VTC. Prophylactic application of the cream was initiated on Day 1 and continued every day until 2 weeks after the end of treatment. Both agents were symmetrically applied within the irradiated field five times a day, and the acute skin reactions were assessed twice weekly in accordance with the Radiation Therapy Oncology Group scores by an investigator who was unaware of the details. The incidence of radiodermatitis increased with the exposure to radiation and was the highest in both groups at Week 7. However, a significant reduction in grades of dermatitis were seen in cohorts applying VTC at all time points, including 2 weeks post radiotherapy (p < 0.015 to p < 0.001). The occurrence of Grade 3 dermatitis was lower in the cohorts using VTC and was statistically significant (p < 0.01). Additionally, follow-up observations 2 weeks after the completion of radiotherapy also showed a reduced degree of radiodermatitis in cohorts applying VTC, which was significant (p = 0.015). VTC is shown to be effective in preventing radiodermatitis and needs to be validated in larger double-blind trials. For the first time, this study shows that the turmeric- and sandal oil-based cream was effective in preventing radiation-induced dermatitis.


Sleep disturbances decrease self-assessed quality of life in individuals who have undergone cystectomy.
The best possible urinary diversion after cystectomy, if any, is yet to be defined to our knowledge. Therefore, we investigated nocturnal urinary disturbances and quality of life in individuals who have undergone cystectomy with urinary diversion for bladder cancer. All patients 30 to 80 years old who had undergone cystectomy with urinary diversion at 7 urological centers in Sweden were included in the study. Sleep disturbances, nocturnal urinary leakage and urine evacuation frequency, as well as their effect on self-assessed quality of life variables were measured with a study specific questionnaire. We received the questionnaire from 452 (92%) of 491 identified individuals. Outcome variables were dichotomized and the results are presented as relative risks. Those individuals with an orthotopic neobladder had an increased risk of nocturnal urinary leakage and/or urine evacuation frequency compared to those with a noncontinent urostomy or cutaneous continent reservoir. Of the patients with an orthotopic neobladder 37% reported negative effects on nocturnal sleep compared to 22% and 14% of those with a noncontinent or continent urostomy, respectively. Of those patients reporting that the urinary diversion had a negative effect on nocturnal sleep 88% had a decreased quality of life vs 65% of those who stated that the urinary diversion had no or little influence on nocturnal sleep. Nocturnal urinary problems are of great concern for individuals with urinary diversion, especially those with an orthotopic neobladder. Regular disruption of sleep decreases quality of life.


Methods for Detecting PER2:LUCIFERASE Bioluminescence Rhythms in Freely Moving Mice.
Circadian rhythms are driven by daily oscillations of gene expression. An important tool for studying cellular and tissue circadian rhythms is the use of a gene reporter, such as bioluminescence from the reporter gene luciferase controlled by a rhythmically expressed gene of interest. Here we describe methods that allow measurement of circadian bioluminescence from a freely moving mouse housed in a standard cage. Using a LumiCycle In Vivo (Actimetrics), we determined conditions that allow detection of circadian rhythms of bioluminescence from the PER2 reporter, PER2::LUC, in freely behaving mice. The LumiCycle In Vivo applies a background subtraction that corrects for effects of room temperature on photomultiplier tube (PMT) output. We tested delivery of d-luciferin via a subcutaneous minipump and in the drinking water. We demonstrate spikes in bioluminescence associated with drinking bouts. Further, we demonstrate that a synthetic luciferase substrate, CycLuc1, can support circadian rhythms of bioluminescence, even when delivered at a lower concentration than d-luciferin, and can support longer-term studies. A small difference in phase of the PER2::LUC bioluminescence rhythms, with females phase leading males, can be detected with this technique. We share our analysis scripts and suggestions for further improvements in this method. This approach will be straightforward to apply to mice with tissue-specific reporters, allowing insights into responses of specific peripheral clocks to perturbations such as environmental or pharmacological manipulations.