Evidence for the horizontal transfer of an integrase gene from a fusellovirus to a pRN-like plasmid within a single strain of Sulfolobus and the implications for plasmid survival.
A fusellovirus SSV4 and a pRN-like plasmid pXZ1 were co-isolated from a single strain of Sulfolobus. In contrast to the previously characterized virus-plasmid hybrids pSSVx and pSSVi, which can coexist intracellulary with a fusellovirus, pXZ1 is not packaged into viral particles and shows no viral infectivity. The virus and plasmid carry genomes of 15 135 and 6970 bp, respectively. For SSV4, 33 predicted ORFs are compactly organized with a strong preference for UGA stop codons, three-quarters of which overlap with either the Shine-Dalgarno motif or the start codon of the following gene. pXZ1 carries seven ORFs, three of which encode an atypical RepA, a PlrA and a CopG protein. A fourth ORF exhibits a high nucleotide sequence identity to the SSV4 integrase gene, which suggests that it has been transferred to the plasmid from SSV4. A single point mutation within an otherwise identical 500 bp region of the integrase gene occurs in the viral attachment site (attP), which corresponds to the anticodon region of the targeted tRNA gene in the host chromosome. This point mutation confers on pXZ1 the ability to integrate into the tRNA(Glu)[CUC] gene, which differs from the integration site of SSV4, tRNA(Glu)[UUC]. SSV4 and pXZ1 were also shown experimentally to integrate into separate sites on the host chromosome. This is believed to be the first report of a pRN plasmid sharing its natural host with a fusellovirus and carrying a highly similar integrase gene.


Increasing mitigation ambition to meet the Paris Agreement's temperature goal avoids substantial heat-related mortality in U.S. cities.
Current greenhouse gas mitigation ambition is consistent with ~3°C global mean warming above preindustrial levels. There is a clear need to strengthen mitigation ambition to stabilize the climate at the Paris Agreement goal of warming of less than 2°C. We specify the differences in city-level heat-related mortality between the 3°C trajectory and warming of 2° and 1.5°C. Focusing on 15 U.S. cities where reliable climate and health data are available, we show that ratcheting up mitigation ambition to achieve the 2°C threshold could avoid between 70 and 1980 annual heat-related deaths per city during extreme events (30-year return period). Achieving the 1.5°C threshold could avoid between 110 and 2720 annual heat-related deaths. Population changes and adaptation investments would alter these numbers. Our results provide compelling evidence for the heat-related health benefits of limiting global warming to 1.5°C in the United States.


Short-term studies underestimate 30-generation changes in a butterfly metapopulation.
Most studies of rare and endangered species are based on work carried out within one generation, or over one to a few generations of the study organism. We report the results of a study that spans 30 generations (years) of the entire natural range of a butterfly race that is endemic to 35 km(2) of north Wales, UK. Short-term studies (surveys in single years and dynamics over 4 years) of this system led to the prediction that the regional distribution would be quite stable, and that colonization and extinction dynamics would be relatively unimportant. However, a longer-term study revealed unexpectedly high levels of population turnover (local extinction and colonization), affecting 18 out of the 20 patches that were occupied at any time during the period. Modelling the system (using the 'incidence function model' (IFM) for metapopulations) also showed higher levels of colonization and extinction with increasing duration of the study. The longer-term dynamics observed in this system can be compared, at a metapopulation level, with the increased levels of variation observed with increasing time that have been observed in single populations. Long-term changes may arise from local changes in the environment that make individual patches more or less suitable for the butterfly, or from unusual colonization or extinction events that take metapopulations into alternative states. One implication is that metapopulation and population viability analyses based on studies that cover only a few animal or plant generations may underestimate extinction threats.


Common variants in 40 genes assessed for diabetes incidence and response to metformin and lifestyle intervention in the diabetes prevention program.
Genome-wide association studies have begun to elucidate the genetic architecture of type 2 diabetes. We examined whether single nucleotide polymorphisms (SNPs) identified through targeted complementary approaches affect diabetes incidence in the at-risk population of the Diabetes Prevention Program (DPP) and whether they influence a response to preventive interventions. We selected SNPs identified by prior genome-wide association studies for type 2 diabetes and related traits, or capturing common variation in 40 candidate genes previously associated with type 2 diabetes, implicated in monogenic diabetes, encoding type 2 diabetes drug targets or drug-metabolizing/transporting enzymes, or involved in relevant physiological processes. We analyzed 1,590 SNPs for association with incident diabetes and their interaction with response to metformin or lifestyle interventions in 2,994 DPP participants. We controlled for multiple hypothesis testing by assessing false discovery rates. We replicated the association of variants in the metformin transporter gene SLC47A1 with metformin response and detected nominal interactions in the AMP kinase (AMPK) gene STK11, the AMPK subunit genes PRKAA1 and PRKAA2, and a missense SNP in SLC22A1, which encodes another metformin transporter. The most significant association with diabetes incidence occurred in the AMPK subunit gene PRKAG2 (hazard ratio 1.24, 95% CI 1.09-1.40, P = 7 × 10(-4)). Overall, there were nominal associations with diabetes incidence at 85 SNPs and nominal interactions with the metformin and lifestyle interventions at 91 and 69 mostly nonoverlapping SNPs, respectively. The lowest P values were consistent with experiment-wide 33% false discovery rates. We have identified potential genetic determinants of metformin response. These results merit confirmation in independent samples.


Systematic identification of genes that regulate neuronal wiring in the Drosophila visual system.
Forward genetic screens in model organisms are an attractive means to identify those genes involved in any complex biological process, including neural circuit assembly. Although mutagenesis screens are readily performed to saturation, gene identification rarely is, being limited by the considerable effort generally required for positional cloning. Here, we apply a systematic positional cloning strategy to identify many of the genes required for neuronal wiring in the Drosophila visual system. From a large-scale forward genetic screen selecting for visual system wiring defects with a normal retinal pattern, we recovered 122 mutations in 42 genetic loci. For 6 of these loci, the underlying genetic lesions were previously identified using traditional methods. Using SNP-based mapping approaches, we have now identified 30 additional genes. Neuronal phenotypes have not previously been reported for 20 of these genes, and no mutant phenotype has been previously described for 5 genes. The genes encode a variety of proteins implicated in cellular processes such as gene regulation, cytoskeletal dynamics, axonal transport, and cell signalling. We conducted a comprehensive phenotypic analysis of 35 genes, scoring wiring defects according to 33 criteria. This work demonstrates the feasibility of combining large-scale gene identification with large-scale mutagenesis in Drosophila, and provides a comprehensive overview of the molecular mechanisms that regulate visual system wiring.


Meaningful involvement of people living with HIV/AIDS in Uganda through linkages between network groups and health facilities: an evaluation study.
While community-based groups are able to provide vital support to people living with HIV/AIDS (PLHIV), their organizational and technical capacities are limited, and they frequently operate in isolation from PLHIV groups. We evaluated a three-year project implemented by the International HIV/AIDS Alliance in Uganda to increase the involvement of PLHIV in the HIV/AIDS response and to improve access to and utilization of prevention, treatment, care, and support services for households affected by HIV/AIDS. Information sources included project monitoring data, interviews with 113 key informants, and 17 focus group discussions in 11 districts. The evaluation found that PLHIV groups reached large numbers of people with education and awareness activities and made a growing number of referrals to health facilities and community-based services. The project trained individuals living openly with HIV as service providers in the community and at designated health facilities. Their presence helped to reduce the stigma that previously deterred PLHIV from seeking care and encouraged individuals to disclose their HIV status to spouses and family members. The project has put into practice the widely endorsed principles of greater and meaningful involvement of PLHIV in a systematic manner and on a large scale. A wide audience--ranging from grassroots PLHIV networks and AIDS service organizations to national-level non-governmental organizations, government agencies, and international organizations--can benefit from the lessons learned.


Degradable polymer prodrugs with adjustable activity from drug-initiated radical ring-opening copolymerization.
Degradable polymer prodrugs based on gemcitabine (Gem) as an anticancer drug were synthesized by 'drug-initiated' nitroxide-mediated radical ring-opening copolymerization (NMrROP) of methacrylic esters and 2-methylene-4-phenyl-1,3-dioxolane (MPDL). Different structural parameters were varied to determine the best biological performances: the nature of the monomer [i.e., oligo(ethylene glycol) methacrylate (OEGMA) or methyl methacrylate (MMA)], the nature of the Gem-polymer linker (i.e., amide or amide and diglycolate) and the MPDL content in the copolymer. Depending on the nature of the methacrylate monomer, two small libraries of water-soluble copolymer prodrugs and nanoparticles were obtained (M n ∼10 000 g mol-1, Đ = 1.1-1.5), which exhibited tunable hydrolytic degradation under accelerated conditions governed by the MPDL content. Drug-release profiles in human serum and in vitro anticancer activity on different cell lines enabled preliminary structure-activity relationships to be established. The cytotoxicity was independently governed by: (i) the MPDL content - the lower the MPDL content, the greater the cytotoxicity; (ii) the nature of the linker - the presence of a labile diglycolate linker enabled a greater Gem release compared to a simple amide bond and (iii) the hydrophilicity of the methacrylate monomer-OEGMA enabled a greater anticancer activity to be obtained compared to MMA-based polymer prodrugs. Remarkably, the optimal structural parameters enabled reaching the cytotoxic activity of the parent (free) drug.


Spectrometric measurement in laryngeal cancer.
Only early diagnosis of laryngeal cancer can prevent major or mutilating treatment. Recently, autofluorescence endoscopy has been developed to enhance endoscopic information and succeeded in facilitating the detection and demarcation of precancerous lesions, carcinoma in situ and cancer of the larynx. The aim of the present study is to quantify autofluorescence imaging by spectroscopy in order to validate the above mentioned findings. In a prospective study, 42 patients with suspected one-sided precancerous or cancerous lesions of the vocal folds were investigated during microlaryngoscopy. Autofluorescence (AF) was induced by filtered blue light (375-440 nm) of a xenon short arc lamp and processed by a CCD camera system (D-light AF System, STORZ, Germany). Autofluorescence images were gathered in a contact mode. For spectrometric measurements an optical multi channel analyzer (AVS-USB 2000, Avantes, The Netherlands) was applied. The results were compared to pathohistological findings. Under blue light excitation normal mucosa presented a bright green fluorescence. Intensity increased from the ventricular folds to the subglottic area. Averaged spectra of the normal laryngeal mucosa demonstrated different fluorescence maxima at 475, 515, 550, 600 and 630 nm. Highest intensity was measured at 515 nm explaining the green appearance of the autofluorescence picture. In contrast, precancerous as well as cancerous lesions showed a significant decrease in autofluorescence intensity with a reddish-violet color. Highest loss of autofluorescence intensity was measured at 515 nm. At this wave length intensity dropped 70% on average in comparison to the regularly appearing contralateral vocal fold. In contrast to 515 nm, the loss of intensity at 630 nm amounted to 38%. Sensitivity amounted to 97% and specificity to 82%. Comparable to autofluorescence endoscopy a differentiation between precancerous and cancerous lesions could not be detected. The reason for the loss of autofluorescence may predominantly be caused by mucosal thickening but also by changes in metabolism and higher nuclei density.


Three-locus linkage analysis using recombinant inbred strains and Bayes' theorem.
Recombinant inbred (RI) strains are useful in linkage analysis and gene mapping. However, the generally small number of strains in an RI strain set limits the power of RI strains in linkage detection. Several methods for increasing the power of RI strains have been used, including summing data across RI strain sets and excluding linkage to genomic regions. In this paper, Bayesian analysis is applied to three-locus linkage data. This method further increases the power of RI strains to detect linkage and gives estimations of the probability of each of the three possible gene orders if the test locus is linked to the pair of marker loci. Several examples are presented, including reconsideration of the position of the proto-oncogene L-myc on the mouse linkage map.


Acoustic markers to differentiate gender in prepubescent children's speaking and singing voice.
Investigation sought to determine whether there is any acoustic variable to objectively differentiate gender in children with normal voices. A total of 30 children, 15 boys and 15 girls, with perceptually normal voices were examined. They were between 7 and 10 years old (mean: 8.1, SD: 0.7 years). Subjects were required to perform the following phonatory tasks: (1) to phonate sustained vowels [a:], [i:], [u:], (2) to read a phonetically balanced text, and (3) to sing a song. Acoustic analysis included long-term average spectrum (LTAS), fundamental frequency (F0), speaking fundamental frequency (SFF), equivalent continuous sound level (Leq), linear predictive code (LPC) to obtain formant frequencies, perturbation measures, harmonic to noise ratio (HNR), and Cepstral peak prominence (CPP). Auditory perceptual analysis was performed by four blinded judges to determine gender. No significant gender-related differences were found for most acoustic variables. Perceptual assessment showed good intra and inter rater reliability for gender. Cepstrum for [a:], alpha ratio in text, shimmer for [i:], F3 in [a:], and F3 in [i:], were the parameters that composed the multivariate logistic regression model to best differentiate male and female children's voices. Since perceptual assessment reliably detected gender, it is likely that other acoustic markers (not evaluated in the present study) are able to make clearer gender differences. For example, gender-specific patterns of intonation may be a more accurate feature for differentiating gender in children's voices.


Characterization and effect of biofouling on polyamide reverse osmosis and nanofiltration membrane surfaces.
Biofouling is a major reason for flux decline in the performance of membrane-based water and wastewater treatment plants. Initial biochemical characterization of biofilm formation potential and biofouling on two commercially available membrane surfaces from FilmTec Corporation were investigated without filtration in laboratory rotating disc reactor systems. These surfaces were polyamide aromatic thin-film reverse osmosis (RO) (BW30) and semi-aromatic nanofiltration (NF270) membranes. Membrane swatches were fixed on removable coupons and exposed to water with indigenous microorganisms supplemented with 1.5 mg l(-1) organic carbon under continuous flow. After biofilms formed, the membrane swatches were removed for analyses. Staining and epifluorescence microscopy revealed more cells on the RO than on the NF surface. Based on image analyses of 5-μm thick cryo-sections, the accumulation of hydrated biofoulants on the RO and NF surfaces exceeded 0.74 and 0.64 μm day(-1), respectively. As determined by contact angle the biofoulants increased the hydrophobicity up to 30° for RO and 4° for NF surfaces. The initial difference between virgin RO and NO hydrophobicities was ∼5°, which increased up to 25° after biofoulant formation. The initial roughness of RO and NF virgin surfaces (75.3 nm and 8.2 nm, respectively) increased to 48 nm and 39 nm after fouling. A wide range of changes of the chemical element mass percentages on membrane surfaces was observed with X-ray photoelectron spectroscopy. The initial chemical signature on the NF surface was better restored after cleaning than the RO membrane. All the data suggest that the semi-aromatic NF surface was more biofilm resistant than the aromatic RO surface. The morphology of the biofilm and the location of active and dead cell zones could be related to the membrane surface properties and general biofouling accumulation was associated with changes in the surface chemistry of the membranes, suggesting the validity of the combination of these novel approaches for initial assessment of membrane performance.


Psychological distress among Thai migrant workers in Israel.
The purpose of this cross-sectional study was to examine the associations between migration stressors and psychological distress among Thai migrant agricultural workers in Israel, and to examine the direct and indirect contribution of socio-cultural variables to this relationship. Two hundred and twenty-one Thai male workers were interviewed using a structured questionnaire that included demographic variables and occupational exposures to organophosphate pesticides (as control variables), migration stressors, intervening variables (traditional health beliefs, social support, drinking behavior, and utilization of medical services), and a psychological distress scale. In multivariate analysis, migration stressors, the migrants' traditional health beliefs, quality of current social relationships, drinking behavior, as well as age and occupational exposure were significantly associated with psychological distress. Workers who reported higher migration stressors (perceived the migration to be difficult, and often felt homesick), those with higher levels of traditional health beliefs, those whose social relationships with other Thai co-workers were poor, those who consumed either no alcohol or large amounts of alcohol, and those who reported 'problem drinking' had significantly higher levels of psychological distress. A moderating effect of the quality of social relationships with co-workers on the association between homesickness and psychological distress was found. Additionally, migrants aged 28-34 and those who were experiencing eye irritation from chemicals at work had significantly increased levels of distress. The findings demonstrate the focal role of specific migration stressors and the current socio-cultural context on psychological distress of migrant workers.


A multi-scale cardiovascular system model can account for the load-dependence of the end-systolic pressure-volume relationship.
The end-systolic pressure-volume relationship is often considered as a load-independent property of the heart and, for this reason, is widely used as an index of ventricular contractility. However, many criticisms have been expressed against this index and the underlying time-varying elastance theory: first, it does not consider the phenomena underlying contraction and second, the end-systolic pressure volume relationship has been experimentally shown to be load-dependent. In place of the time-varying elastance theory, a microscopic model of sarcomere contraction is used to infer the pressure generated by the contraction of the left ventricle, considered as a spherical assembling of sarcomere units. The left ventricle model is inserted into a closed-loop model of the cardiovascular system. Finally, parameters of the modified cardiovascular system model are identified to reproduce the hemodynamics of a normal dog. Experiments that have proven the limitations of the time-varying elastance theory are reproduced with our model: (1) preload reductions, (2) afterload increases, (3) the same experiments with increased ventricular contractility, (4) isovolumic contractions and (5) flow-clamps. All experiments simulated with the model generate different end-systolic pressure-volume relationships, showing that this relationship is actually load-dependent. Furthermore, we show that the results of our simulations are in good agreement with experiments. We implemented a multi-scale model of the cardiovascular system, in which ventricular contraction is described by a detailed sarcomere model. Using this model, we successfully reproduced a number of experiments that have shown the failing points of the time-varying elastance theory. In particular, the developed multi-scale model of the cardiovascular system can capture the load-dependence of the end-systolic pressure-volume relationship.


Parental origin of the extra chromosome in the cat eye syndrome: evidence from heteromorphism and in situ hybridization analysis.
Two individuals, a boy and girl, with a clinical diagnosis of cat eye syndrome had an extra bisatellited chromosome. In the girl, the diagnosis was made on the basis of coloboma of the right iris, right preauricular pit, and imperforate anus; in the boy, bilateral colobomata of the iris, down-slanting palpebral fissures, right preauricular skin tag, and right preauricular pit. Multiple staining techniques were used to characterize the extra chromosomes. With G-banding the extra chromosome usually appeared monocentric with two major G-positive bands, but with satellites on both ends; with C-banding, two C-band positive regions were evident, indicating that the chromosomes were likely dicentric. Silver staining demonstrated the presence of NORs near each end; Q-banding showed satellites on each end, differing in brightness and size. The chromosomes of the parents were normal; comparisons of Q-band heteromorphisms of the acrocentric chromosomes of the parents with those of the extra chromosome showed in each case one short arm/satellite region of the extra chromosome identical in appearance to one chromosome 22 of the mother and the other end of the extra bisatellited chromosome identical to the short arm/satellite of the mother's second chromosome 22. This extra chromosome, then, is the result of a maternal meiotic error in each case. In situ hybridization studies using the chromosome 22-derived probe p22/34, which identifies locus D22S9, showed 16% of the cells from the female patient to have silver grains on the proximal long arm of the normal chromosome 22 and 14% on the extra chromosome, while 10% of cells from the male had grains on the normal chromosomes 22 and an equal number on the extra chromosome, confirming the chromosome 22 origin of the extra chromosome in these patients.


Individual and population level impact of chronic conditions on functional disability in older adults.
It is unknown if the relationship between multimorbidity and disability differs by combinations of chronic conditions. The objective of our study was to elucidate how joint effect of different combinations of chronic conditions impact the five year risk of functional disability at the population level. Participants ≥65 years from the Canadian Study of Health and Aging were assessed for functional disability measured using activities of daily living (ADL) and instrumental ADL (IADL), and the presence of conditions in five disease domains; cardiometabolic, neurological, sensory, musculoskeletal, and respiratory. Logistic regression was used to assess the relationship between each disease domain and incident ADL and IADL measured at five years of follow up and population attributable risk (PAR) was modeled for diseases domains that were significantly associated with disability. Results were stratified by sex and age (65-74 years, ≥75 years). There were 6272 participants free of ADL disability and 4571 participants free from IADL disability at baseline. For incident ADL, the greatest PAR values were 21.3 (9.8-32.8) for the cardiometabolic domain in males 65-74 years, 22.7 (4.7-40.8) for the musculoskeletal domain for females aged 65-74 years, and 11.2 (2.8-19.7) for the musculoskeletal domain in males ≥75 years. The PAR for the musculoskeletal, sensory, and neurological domains were similar in females ≥75 years(9.3-9.9). PAR values were lower but followed similar patterns for IADL disability. The chronic disease domains which most strongly predicted incident ADLs and IADLs did not account for the greatest amount of disability at the population level.


Cardiac emergency preparedness in health/fitness facilities in Australia.
Health/fitness facilities are popular venues for physical activity, where increasingly more individuals at risk of cardiovascular events exercise to achieve positive health outcomes. The aim of our study was to analyze cardiac emergency preparedness in health/fitness facilities in Queensland, Australia. Cross-sectional survey of health/fitness facilities in Queensland. A risk management questionnaire was administered over 7 months, July 2009 to January 2010, using an online or paper-based version. The data are presented as the proportion of survey respondents giving specific responses to questionnaire items related to cardiac emergency preparedness, especially the provision of automated external defibrillators (AEDs). Fifty-two health/fitness facility managers responded to the survey. Most of the surveyed facilities conducted pre-activity screening (92%). Of those with a written emergency plan (79%), only 37% physically rehearsed their emergency response systems at regular intervals. Ninety-five percent of the facilities had fitness employees with a current first aid/cardiopulmonary resuscitation certificate and training. Of the 10 (19%) facilities with an on-site AED, only 6 had staff qualified to use the AED in an emergency, and only 6 had the AED as part of a public access defibrillator program. This is the first study to report that cardiac emergency preparedness is not optimal in the health/fitness facilities in Australia. Development of policies and procedures for training health/fitness professionals in emergency procedures is needed to minimize the risk when exercise-induced cardiac events occur at health/fitness facilities.


Disadvantages of using the area under the receiver operating characteristic curve to assess imaging tests: a discussion and proposal for an alternative approach.
The objectives are to describe the disadvantages of the area under the receiver operating characteristic curve (ROC AUC) to measure diagnostic test performance and to propose an alternative based on net benefit. We use a narrative review supplemented by data from a study of computer-assisted detection for CT colonography. We identified problems with ROC AUC. Confidence scoring by readers was highly non-normal, and score distribution was bimodal. Consequently, ROC curves were highly extrapolated with AUC mostly dependent on areas without patient data. AUC depended on the method used for curve fitting. ROC AUC does not account for prevalence or different misclassification costs arising from false-negative and false-positive diagnoses. Change in ROC AUC has little direct clinical meaning for clinicians. An alternative analysis based on net benefit is proposed, based on the change in sensitivity and specificity at clinically relevant thresholds. Net benefit incorporates estimates of prevalence and misclassification costs, and it is clinically interpretable since it reflects changes in correct and incorrect diagnoses when a new diagnostic test is introduced. ROC AUC is most useful in the early stages of test assessment whereas methods based on net benefit are more useful to assess radiological tests where the clinical context is known. Net benefit is more useful for assessing clinical impact. • The area under the receiver operating characteristic curve (ROC AUC) measures diagnostic accuracy. • Confidence scores used to build ROC curves may be difficult to assign. • False-positive and false-negative diagnoses have different misclassification costs. • Excessive ROC curve extrapolation is undesirable. • Net benefit methods may provide more meaningful and clinically interpretable results than ROC AUC.


Isolation and characterization of a large, neurite-associated glycoconjugate from neuroblastoma cells.
A high molecular weight glycoconjugate has been isolated from neurite-producing neuronal tumor cells in culture and has been designated as I(0) based on its elution characteristics in gel filtration chromatography. This molecule cannot be found in a variety of nonneuronal cells. I(0) is found in the substratum-attached material or cell fraction of neurite-producing neuroblastoma cells, depending upon culture conditions. It is found in the substratum-bound fraction of B104 rat neuroblastoma cells during serum starvation and in the EGTA-detached cell fraction of B104 cells grown in chemically defined N2 medium. It occurs only in the cell fraction of the human neuroblastoma line Platt. Examination of behavioral variants of the B104 rat line further strengthens the association of I(0) with neurite production; the constitutive neurite-producing E(R)B9 variant contains I(0) while the non-neurite-producing E(R)A11 variant does not. I(0) is large, eluting in the void volume of sepharose-CL2B columns. Radioiodination of intact cells with lactoperoxidase shows I(0) to be a cell surface component. Metabolic radiolabeling studies show that it contains a high proportion of polysaccharide to protein, does not contain mannose, and is unsulfated. Alkaline borohydride reduction release two size classes of large polysaccharide chain. The alkaline reduction results, along with the mannose incorporation studies, show the presence of O-glycosidic linkages and few, if any, N-linkages. Resistance to nitrous acid deamination, insensitivity to glycosaminoglycan lyases, and the absence of sulfation, indicate that I(0) does not contain the glycosaminoglycans hyaluronic acid, chondroitin-, dermatan-, or heparin- sulfates. Affinity column chromatography reveals high binding affinity of I(0) to polyornithine and no binding to gelatin (collagen) or the glycosaminoglycans hyaluronate and heparin. These studies describe a unique high molecular weight glycoconjugate on the surface of neurite-producing neuroblastoma cell lines from two species.


Natural Environments and Childhood Experiences Promoting Physical Activity, Examining the Mediational Effects of Feelings about Nature and Social Networks.
The importance of natural environments (NEs) for physical activity (PA) has been studied extensively. However, there is scant evidence to explain the motivational processes underlying the NE-PA relation. The aim of this study was to investigate the NE-PA relation using an ecological framework, focusing on perception of NEs, childhood experiences and possible intra- and inter-individual mediators. Data were retrieved from a cross-sectional survey among 2168 adults from all over Norway. In addition, the coverage of NEs by municipalities was retrieved from national registers. Logistic regression showed that, unlike the self-reported proximity to NEs, higher ratings of perceived supportiveness of NEs for PA predicted participation in NE-based PA for at least 60 min/week or 150 min/week, before and after controlling for socio-demographic characteristics. Reporting frequent experiences in nature during childhood was also an important predictor of higher levels of NE-based PA. Furthermore, a mediational analysis showed that the effect of both predictors was mediated by "feelings about nature" and "social networks". These findings indicate that to encourage the use of local NE for PA, not only should environmental perceptions be taken into account, positive feelings towards nature alongside opportunities to share activity in nature with others should also be promoted.


Comparison of functional recovery of manual dexterity after unilateral spinal cord lesion or motor cortex lesion in adult macaque monkeys.
In relation to mechanisms involved in functional recovery of manual dexterity from cervical cord injury or from motor cortical injury, our goal was to determine whether the movements that characterize post-lesion functional recovery are comparable to original movement patterns or do monkeys adopt distinct strategies to compensate the deficits depending on the type of lesion? To this aim, data derived from earlier studies, using a skilled finger task (the modified Brinkman board from which pellets are retrieved from vertical or horizontal slots), in spinal cord and motor cortex injured monkeys were analyzed and compared. Twelve adult macaque monkeys were subjected to a hemi-section of the cervical cord (n = 6) or to a unilateral excitotoxic lesion of the hand representation in the primary motor cortex (n = 6). In addition, in each subgroup, one half of monkeys (n = 3) were treated for 30 days with a function blocking antibody against the neurite growth inhibitory protein Nogo-A, while the other half (n = 3) represented control animals. The motor deficits, and the extent and time course of functional recovery were assessed. For some of the parameters investigated (wrist angle for horizontal slots and movement types distribution for vertical slots after cervical injury; movement types distribution for horizontal slots after motor cortex lesion), post-lesion restoration of the original movement patterns ("true" recovery) led to a quantitatively better functional recovery. In the motor cortex lesion groups, pharmacological reversible inactivation experiments showed that the peri-lesion territory of the primary motor cortex or re-arranged, spared domain of the lesion zone, played a major role in the functional recovery, together with the ipsilesional intact premotor cortex.


Instantaneous Decrease in Left Ventricular Afterload during Transcatheter Aortic Valve Implantation Results in Immediate Changes in Left Ventricular Strain.
Severe aortic stenosis causes chronic increased afterload on the left ventricle (LV) resulting in myocardial hypertrophy and ultimately dysfunction if left untreated. Transcatheter aortic valve implantation (TAVI) immediately decreases the afterload on the LV by reducing the pressure gradient through the aortic valve. In our study, we aim to evaluate immediate changes in LV mechanics using intra-procedural transesophageal echocardiography (TEE) to assess circumferential and radial strain via speckle tracking. Intra-operative TEE was performed during TAVI for 53 patients (mean age 84 ± 8 years). Two-dimensional images in the transgastric view were acquired at the level of the papillary muscle. Circumferential and radial strain was calculated using speckle tracking with Philips Qlab software. Global LV afterload was measured by calculating valvulo-arterial impedance (Zva). Immediately post-TAVI, there was a change in both radial strain rate (Pre: 0.73 ± 0.04 vs. Post: 0.88 ± 0.04 per second, P < 0.001) and circumferential strain rate (-0.53 ± 0.04 (pre) vs. -0.74 ± 0.04 (post) per second, P < 0.001). There was also an immediate improvement in circumferential global strain parameters (-14.5 ± 5% (pre) vs. -16.0 ± 4.7% (post), P < 0.05), whereas there was no significant change seen in global radial strain (15.6 ± 0.8% (pre) vs. 15.2 ± 0.9% (post), P = 0.69). No significant change was seen in LV ejection fraction (51.5 ± 14.2% (pre) vs. 52.1 ± 14.0% (post), P = 0.77). Speckle tracking using TEE images is feasible and identifies significant improvements in LV strain and strain rate immediately following TAVI that is not detected by conventional measure of LV function.


Astragalus root and elderberry fruit extracts enhance the IFN-β stimulatory effects of Lactobacillus acidophilus in murine-derived dendritic cells.
Many foods and food components boost the immune system, but little data are available regarding the mechanisms by which they do. Bacterial strains have disparate effects in stimulating the immune system. In dendritic cells, the gram-negative bacteria Escherichia coli upregulates proinflammatory cytokines, whereas gram-positive Lactobacillus acidophilus induces a robust interferon (IFN)-β response. The immune-modulating effects of astragalus root and elderberry fruit extracts were examined in bone marrow-derived murine dendritic cells that were stimulated with L. acidophilus or E. coli. IFN-β and other cytokines were measured by ELISA and RT-PCR. Endocytosis of fluorescence-labeled dextran and L. acidophilus in the presence of elderberry fruit or astragalus root extract was evaluated in dendritic cells. Our results show that both extracts enhanced L. acidophilus-induced IFN-β production and slightly decreased the proinflammatory response to E. coli. The enhanced IFN-β production was associated with upregulation of toll-like receptor 3 and to a varying degree, the cytokines IL-12, IL-6, IL-1β and TNF-α. Both extracts increased endocytosis in immature dendritic cells, and only slightly influenced the viability of the cells. In conclusion, astragalus root and elderberry fruit extracts increase the IFN-β inducing activity of L. acidophilus in dendritic cells, suggesting that they may exert antiviral and immune-enhancing activity.


Nanoscale Charge-Balancing Mechanism in Alkali-Substituted Calcium-Silicate-Hydrate Gels.
Alkali-activated materials and related alternative cementitious systems are sustainable technologies that have the potential to substantially lower the CO2 emissions associated with the construction industry. However, these systems have augmented chemical compositions as compared to ordinary Portland cement (OPC), which may impact the evolution of the hydrate phases. In particular, calcium-silicate-hydrate (C-S-H) gel, the main hydrate phase in OPC, is likely to be altered at the atomic scale due to changes in the bulk chemical composition, specifically via the addition of alkalis (i.e., Na or K) and aluminum. Here, via density functional theory calculations, we reveal the presence of a charge balancing mechanism at the molecular level in C-S-H gel (as modeled using crystalline 14 Å tobermorite) when alkalis and aluminum atoms are introduced into the structure. Different structural representations are obtained depending on the level of substitution and the degree of charge balancing incorporated in the structures. The impact of these substitutional and charge balancing effects on the structures is assessed by analyzing the formation energies, local bonding environments, diffusion barriers and mechanical properties. The results of this computational study provide information on the phase stability of alkali/aluminum containing C-S-H gels, shedding light on the fundamental atomic level mechanisms that play a crucial role in these complex disordered materials.


Simultaneous evaluation of renal morphology and function in live kidney donors using dynamic magnetic resonance imaging.
Evaluation of potential kidney donors requires the assessment of both kidney anatomy and function. In this prospective study, we sought to expand the diagnostic yield of magnetic resonance (MR) by adding functional measurements of glomerular filtration rate (GFR) and split renal function. Between 2007 and 2009, all potential kidney donors presenting to our facility underwent a comprehensive single-stop MR study that included an assessment of anatomy, angiography and functional measurements. GFR was measured after a bolus injection of gadobutrol (4 ml, approximately 0.05 mmol/kg) and calculated from the washout of the signal intensity obtained over the liver. Split renal function was calculated from the increase of signal intensity over the renal cortex. Values were compared to renal scintigraphy with (99m)Tc-DTPA from the same day. The MR investigation was successfully performed in 21 participants. The GFR derived from MR (MR-GFR) correlated well (r = 0.84) with the GFR derived from scintigraphy (DTPA-GFR). The mean value of the paired differences was 4 +/- 13 [SD] ml/min/1.73 m(2) and was not significantly different from zero. The ratio between right and left kidney function was similar with both techniques (1.01 +/- 0.17 with MR and 1.06 +/- 0.12 with scintigraphy, P = 0.20). We demonstrate an MR-based approach to comprehensively evaluate both kidney anatomy and function in a single investigation, thereby facilitating the evaluation of potential kidney donors.


Loop flexibility in human telomeric quadruplex small-molecule complexes.
Quadruplex nucleic acids can be formed at the ends of eukaryotic chromosomes. Their formation and stabilisation by appropriate small molecules can be used as a means of inhibiting the telomere maintenance functions of telomerase in human cancer cells. The crystal structures have been determined for a number of complexes between these small molecules and human telomeric DNA and RNA quadruplexes. The detailed structural characteristics of these complexes have been surveyed here and the variations in conformation for the TTA and UUA loops have been explored. Loop conformations have been classified in terms of a number of discrete types and their distribution among the crystal structures. Sugar conformation and backbone angles have also been examined and trends highlighted. One particular loop class has been found to be most prevalent. Implications for in particular, rational drug design, are discussed.


Association of obesity and smoking with PSA and PSA velocity in men with prostate cancer.
Significant number of prostate tumors are slow growing and could probably be left untreated. However, many are aggressive and can spread rapidly causing patient suffering and/or death. Current technology does not allow physicians to differentiate between slow growing and aggressive tumors at diagnosis. Hence, many patients are exposed to invasive treatment and its associated morbidities such as incontinence and impotence. Markers that enable differentiation between slow and fast progressing cancer will allow physicians to prevent unnecessary treatments on men who may not need them, and focus on the men with aggressive disease. A longitudinal study was conducted (N = 140) using mixed effects regression models to determine the association of obesity and smoking toward prostate cancer progression. These models account for correlation because of repeated measures over time, thus, using maximum amount of information provided by the subject. Estimates thus obtained are more robust and reliable than those obtained using data from a single time point. Rate of change of prostate-specific antigen (PSA) over time (PSA velocity) was used as a measure of prostate cancer progression. Results indicate that PSA velocity of overweight and obese subjects (0.59 and 1.05 ng/mL/year) was not significantly different as compared with normal weight subjects (p values .91 and .31, respectively). For men in the highest tertile of pack-years of smoking, PSA velocity was significantly higher as compared with never smokers 1.57 ng/mL/year (p = .04). Further studies with larger sample sizes and study designs specific to above exposures are needed before recommendations can be made to reduce weight or reduce/quit smoking.


An Exact Algorithm to Compute the Double-Cut-and-Join Distance for Genomes with Duplicate Genes.
Computing the edit distance between two genomes is a basic problem in the study of genome evolution. The double-cut-and-join (DCJ) model has formed the basis for most algorithmic research on rearrangements over the last few years. The edit distance under the DCJ model can be computed in linear time for genomes without duplicate genes, while the problem becomes NP-hard in the presence of duplicate genes. In this article, we propose an integer linear programming (ILP) formulation to compute the DCJ distance between two genomes with duplicate genes. We also provide an efficient preprocessing approach to simplify the ILP formulation while preserving optimality. Comparison on simulated genomes demonstrates that our method outperforms MSOAR in computing the edit distance, especially when the genomes contain long duplicated segments. We also apply our method to assign orthologous gene pairs among human, mouse, and rat genomes, where once again our method outperforms MSOAR.


Treatment of Osteoporosis, with a Focus on 2 Monoclonal Antibodies.
Osteoporosis is a common skeletal disease characterized by bone loss and subsequent increased risk of fragility fractures. Recent advances in our mechanistic understanding of molecular communications among osteoblasts, osteoclasts, and osteocytes give insight into the important roles of the canonical Wnt/β-catenin pathway and the RANK/RANKL/OPG pathway in the process of bone remodeling. Due to the translation of the canonical Wnt/β-catenin pathway and the RANK/RANKL/OPG pathway in the regulation of osteoblasts and osteoclasts, new targets have been studied in recent years, such as sclerostin and receptor activator of NF-κB ligand (RANKL). In this review, we first introduce the signaling pathways involved in interactions among osteoblasts, osteoclasts, and osteocytes. Next, we describe clinical trials of denosumab and romosozumab, which are monoclonal antibodies that target RANKL and sclerostin, respectively. We analyze the efficacy of these drugs and provide a profile for the management of osteoporosis.


Therapeutic applications of bioactive sphingolipids in hematological malignancies.
Sphingolipids are sphingosine-based lipid molecules that have important functions in cellular signal transduction and in a variety of cellular processes including proliferation, differentiation, programmed cell death (apoptosis) and responses to stressful conditions. Ceramides, dihydroceramide, sphingosine and sphingosine-1-phosphate are examples of those bioactive sphingolipids. They have a major impact on determination of the cell fate by contributing to the cell survival or cell death through apoptosis. Despite the number of carbon atoms in the fatty acid chain changes the physiological role; ceramides generally exert suppressive roles on the cell proliferation. There have been several enzymes identified in this pathway that are responsible for the conversion of ceramide into other sphingolipid derivatives. Those derivatives also have differential roles on those cellular processes. Sphingosine-1-phosphate is an example of such sphingolipid derivatives which has antiapoptotic effects. As they have significant impacts particularly on the cell death and survival, bioactive sphingolipids have a great potential to be targets in cancer therapy. Increasing number of studies indicates that sphingolipid derivatives are important in the progression of hematological malignancies, and they are also involved in the resistance to current chemotherapeutic options. This review compiles the current knowledge in this area for enlightening the therapeutic potentials of bioactive sphingolipids in various leukemias.


Increased total sodium concentration in gray matter better explains cognition than atrophy in MS.
To investigate whether brain total sodium accumulation assessed by 23Na MRI is associated with cognitive deficit in relapsing-remitting multiple sclerosis (RRMS). Eighty-nine participants were enrolled in the study (58 patients with RRMS with a disease duration ≤10 years and 31 matched healthy controls). Patients were classified as cognitively impaired if they failed at least 2 tasks on the Brief Repeatable Battery. MRI was performed at 3T using 23Na MRI to obtain total sodium concentration (TSC) in the different brain compartments (lesions, normal-appearing white matter [NAWM], gray matter [GM]) and 1H- magnetization-prepared rapid gradient echo to assess GM atrophy (GM fraction). The mean disease duration was 3.1 years and the median Expanded Disability Status Scale score was 1 (range 0-4.5). Thirty-seven patients were classified as cognitively preserved and 21 as cognitively impaired. TSC was increased in GM and NAWM in cognitively impaired patients compared to cognitively preserved patients and healthy controls. Voxel-wise analysis demonstrated that sodium accumulation was mainly located in the neocortex in cognitively impaired patients. Regression analysis evidenced than the 2 best independent predictors of cognitive impairment were GM TSC and age. Receiver operating characteristic analyses demonstrated that sensitivity and specificity of the GM TSC to classify patients according to their cognitive status were 76% and 71%, respectively. This study provides 2 main findings. (1) In RRMS, total sodium accumulation in the GM is better associated with cognitive impairment than GM atrophy; and (2) total sodium accumulation in patients with cognitive impairment is mainly located in the neocortex.


Current status of allergy prevalence in Germany: Position paper of the Environmental Medicine Commission of the Robert Koch Institute.
The lifetime prevalence of allergic diseases in adults in Germany [self-reported doctor diagnosed allergic diseases, Study on Adult Health in Germany (Studie zur Gesundheit Erwachsener in Deutschland, DEGS1, 2008-2011) of the Robert Koch Institute] is 8.6 % for asthma, 14.8 % for hay fever, 3.5 % for atopic dermatitis, 8.1 % for contact dermatitis, 4.7 % for food allergies, and 2.8 % for insect venom allergies. Almost 20 % of German adults are currently affected by at least one allergy. In tests on 50 common single allergens and two mixtures comprising either inhalant allergens or grass pollen allergens, 48.6 % of participants exhibited at least one allergic sensitization (specific IgE antibody detection). Overall, 33.6 % of participants were sensitized to inhalant allergens, 25.5 % to at least one food allergens, and 22.6 % to at least one insect venom allergens. A comparison of data on adults from 1998 [Federal Health Survey 1998 (Bundes-Gesundheitssurvey 1998, BGS98) of the Robert Koch Institute] and 2008-2011 (DEGS1) shows an increase in prevalence over time of almost three percentage points, while the rate of sensitization to inhalant allergens has increased from 29.8 % to 33.6 %. The prevalence of doctor diagnosed hay fever, atopic dermatitis, and food allergies, on the other hand, has remained virtually unchanged over the last 15 years. The Germany-wide lifetime prevalence of allergic diseases in children and adolescents [Study on the Health of Children and Adolescents in Germany (Studie zur Gesundheit von Kindern und Jugendlichen in Deutschland, KiGGS initial survey, 2003-2006) of the Robert Koch Institute] was 4.7 % for asthma, 10.7 % for hay fever, and 13.2 % for atopic dermatitis. Altogether, 40.8 % of German children and adolescents were sensitized to at least one of the inhalant or food allergens measured, while 20.0 % were sensitized to at least one food allergen. A marked increase in hay fever prevalence among East German children in the 1990s has resulted in an alignment of prevalence rates in East and West Germany. In contrast to adults, there was no longer a discernible difference in the prevalence of asthma, hay fever, and allergic sensitization in children between the western and eastern German federal states. In international comparisons with prevalence data from other studies, the participating German centers are in the lower third of the distribution of frequency for both children and adults.


White Rabbit Precision Time Protocol on Long-Distance Fiber Links.
The application of White Rabbit precision time protocol (WR-PTP) in long-distance optical fiber links has been investigated. WR-PTP is an implementation of PTP in synchronous Ethernet optical fiber networks, originally intended for synchronization of equipment within a range of 10 km. This paper discusses the results and limitations of two implementations of WR-PTP in the existing communication fiber networks. A 950-km WR-PTP link was realized using unidirectional paths in a fiber pair between Espoo and Kajaani, Finland. The time transfer on this link was compared (after initial calibration) against a clock comparison by GPS precise point positioning (PPP). The agreement between the two methods remained within [Formula: see text] over three months of measurements. Another WR-PTP implementation was realized between Delft and Amsterdam, the Netherlands, by cascading two links of 137 km each. In this case, the WR links were realized as bidirectional paths in single fibers. The measured time offset between the starting and end points of the link was within 5 ns with an uncertainty of 8 ns, mainly due to the estimated delay asymmetry caused by chromatic dispersion.


Continuous cell supply from Krt7-expressing hematopoietic stem cells during native hematopoiesis revealed by targeted in vivo gene transfer method.
The nature of hematopoietic stem cells under normal hematopoiesis remained largely unknown due to the limited assays available to monitor their behavior in situ. Here, we develop a new mouse model to transfer genes specifically into the primitive hematopoietic stem cell compartment through the utilization of a modified Rcas/TVA system. We succeeded in transferring a GFP reporter gene into adult hematopoietic stem cells in vivo, which are predominantly quiescent, by generating pseudotyped-lentivirus. Furthermore, we demonstrate the utility of this system to study neonatal hematopoiesis, a developmental stage that has been difficult to analyze to date. Using the system developed in this study, we observed continuous multi-lineage hematopoietic cell supply in peripheral blood from Krt7-positive hematopoietic stem cells during unperturbed homeostatic condition. This powerful experimental system could provide a new standard tool to analyze hematopoiesis under physiological condition without transplantation.


Neutron-induced fission of uranium: a dating method for lunar surface material.
Volcanic glasses collected on the rim of Shorty Crater in the Apollo 17 area were formed 3.63 x 10(9) years ago. The amounts of xenon-136 produced by neutron-induced fission of uranium-235 indicate that the glasses resided on the lunar surface for about 38 million years before they were deeply buried. The glass spherules were reexcavated by the impact that formed Shorty Crater 17 million years ago, and remained undisturbed until they were collected.


Differential mechanisms of glucose and palmitate in augmentation of insulin secretion in mouse pancreatic islets.
To assess the possible importance of saturated fatty acids in glucose amplification of K+ATP channel-independent insulin secretion. Insulin release from perifused pancreatic islets of NMRI mice was determined by radioimmunoassay. In the presence of K+ (20 mmol/l) and diazoxide (250 micromol/l), which stimulates Ca2+ influx and opens K+ATP channels, palmitate (165 micromol/l total; 1.2 micromol/l free) increased insulin secretion at 3.3, 10 and 16.7 mmol/l glucose while glucose (10; 16.7 mmol/l) did not increase insulin secretion. In the presence of K+ (60 mmol/l) and diazoxide (250 micromol/l), glucose (10; 16.7 mmol/l) stimulation of K+ATP channel-independent insulin secretion increased, whereas the effectiveness of palmitate (165 micromol/l total; 1.2 micromol/l free) on insulin secretion at both 3.3, 10 or 16.7 mmol/l glucose was reduced. Palmitate thereby mimicked the stimulatory pattern of the protein kinase C activator, 12-O-tetradecanoylphorbol 13-acetate (0.16 micromol/l), which also failed to increase insulin secretion at maximum depolarising concentrations of K+ (60 mmol/l). Furthermore, the protein kinase C inhibitor calphostin C (1 micromol/1), led to a complete suppression of the effects of both palmitate (165 micromol/l total; 1.2 micromol/l free) and myristate (165 micromol/l total; 2.4 micromol/l free) stimulation of glucose (16.7 mmol/l)-induced insulin secretion. Calphostin C (1 micromol/l), however, failed to affect insulin secretion induced by glucose (16.7 mmol/l). These data suggest that glucose could increase insulin secretion independently of saturated fatty acids like palmitate and myristate, which amplify glucose-induced insulin secretion by activation of protein kinase C.


Fabrication and understanding of Cu3Si-Si@carbon@graphene nanocomposites as high-performance anodes for lithium-ion batteries.
Besides silicon's low electronic conductivity, another critical issue for using silicon as the anode for lithium-ion batteries (LIBs) is the dramatic volume variation (>300%) during lithiation/delithiation processes, which can lead to rapid capacity fading and poor rate capability, thereby hampering silicon's practical applications in batteries. To mitigate these issues, herein, we report our findings on the design and understanding of a self-supported Cu3Si-Si@carbon@graphene (Cu3Si-SCG) nanocomposite anode. The nanocomposite is composed of Cu3Si-Si core and carbon shell with core/shell particles uniformly encapsulated by graphene nanosheets anchored directly on a Cu foil. In this design, the carbon shell, the highly elastic graphene nanosheet, and the formed conductive and inactive Cu3Si phase in Si serve as buffer media to suppress volume variation of Si during lithiation/delithiation processes and to facilitate the formation of a stable solid electrolyte interface (SEI) layer as well as to enable good transport kinetics. Chemomechanical simulation results quantitatively coincide with the in situ TEM observations of volume expansion and provide process details not seen in experiments. The optimized Cu3Si-SCG nanocomposite anode exhibits good rate performance and delivers reversible capacity of 483 mA h g-1 (based on the total weight of Cu3Si-SCG) after 500 cycles with capacity retention of about 80% at high current density of 4 A g-1, rendering the nanocomposite a desirable anode candidate for high-performance LIBs.


Influenza Virus Infections and Cellular Kinases.
Influenza A viruses (IAVs) are a major cause of respiratory illness and are responsible for yearly epidemics associated with more than 500,000 annual deaths globally. Novel IAVs may cause pandemic outbreaks and zoonotic infections with, for example, highly pathogenic avian influenza virus (HPAIV) of the H5N1 and H7N9 subtypes, which pose a threat to public health. Treatment options are limited and emergence of strains resistant to antiviral drugs jeopardize this even further. Like all viruses, IAVs depend on host factors for every step of the virus replication cycle. Host kinases link multiple signaling pathways in respond to a myriad of stimuli, including viral infections. Their regulation of multiple response networks has justified actively targeting cellular kinases for anti-cancer therapies and immune modulators for decades. There is a growing volume of research highlighting the significant role of cellular kinases in regulating IAV infections. Their functional role is illustrated by the required phosphorylation of several IAV proteins necessary for replication and/or evasion/suppression of the innate immune response. Identified in the majority of host factor screens, functional studies further support the important role of kinases and their potential as host restriction factors. PKC, ERK, PI3K and FAK, to name a few, are kinases that regulate viral entry and replication. Additionally, kinases such as IKK, JNK and p38 MAPK are essential in mediating viral sensor signaling cascades that regulate expression of antiviral chemokines and cytokines. The feasibility of targeting kinases is steadily moving from bench to clinic and already-approved cancer drugs could potentially be repurposed for treatments of severe IAV infections. In this review, we will focus on the contribution of cellular kinases to IAV infections and their value as potential therapeutic targets.


Extracorporeal shockwave enhanced regeneration of fibrocartilage in a delayed tendon-bone insertion repair model.
Fibrous tissue is often formed in delayed healing of tendon bone insertion (TBI) instead of fibrocartilage. Extracorporeal shockwave (ESW) provides mechanical cues and upregulates expression of fibrocartilage-related makers and cytokines. We hypothesized that ESW would accelerate fibrocartilage regeneration at the healing interface in a delayed TBI healing model. Partial patellectomy with shielding at the TBI interface was performed on 32 female New Zealand White Rabbits for establishing this delayed TBI healing model. The rabbits were separated into the control and ESW group for evaluations at postoperative week 8 and 12. Shielding was removed at week 4 and a single ESW treatment was applied at week 6. Fibrocartilage regeneration was evaluated histomorphologically and immunohistochemically. Vickers hardness of the TBI matrix was measured by micro-indentation. ESW group showed higher fibrocartilage area, thickness, and proteoglycan deposition than the control in week 8 and 12. ESW increased expression of SOX9 and collagen II significantly in week 8 and 12, respectively. ESW group showed a gradual transition of hardness from bone to fibrocartilage to tendon, and had a higher Vickers hardness than the control group at week 12. In conclusion, ESW enhanced fibrocartilage regeneration at the healing interface in a delayed TBI healing model.


Cannabis Use and Disorder From Childhood to Adulthood in a Longitudinal Community Sample With American Indians.
Recent changes in DSM criteria require new documentation of the prevalence and developmental sequences of cannabis use disorder (CUD). The goal of this study was to investigate the early course of DSM-5 CUD and its overlap with DSM-IV and consumption constructs in a community-representative sample of American Indians. Data came from the prospective, longitudinal, population-based Great Smoky Mountains Study in North Carolina (N = 1,420, including 349 American Indians). Cannabis use and disorder were assessed during yearly interviews from 9 to 16 years of age and at 19, 21, 26, and 30 years of age (up to 11 assessments per participant from 1993 through 2015). By 30 years of age, approximately 70% of participants had used cannabis, 34% had used cannabis daily, and 18% had met criteria for DSM-5 CUD. Approximately 1 in 4 cannabis users met criteria for CUD at some point. Those who met criteria initiated use more than 2 years previously (at 13.3 years old) compared with other users. Despite higher risks from increased poverty, American Indians' patterns of use were similar to those of the rest of the sample. Concordance between DSM-5 CUD and DSM-IV abuse or dependence was substantial but was even higher between DSM-5 CUD and daily use. It was common to have used cannabis daily or to have met criteria for DSM-5 CUD by adulthood. DSM-5 CUD was an improvement over DSM-IV diagnostic constructs by raising the threshold for diagnosis.


Sugar-sweetened soft drink consumption and risk of pancreatic cancer in two prospective cohorts.
A history of diabetes mellitus and a diet high in glycemic load are both potential risk factors for pancreatic cancer. Sugar-sweetened soft drinks are a prevalent source of readily absorbable sugars and have been associated with an increased risk of obesity and diabetes. We investigated whether higher consumption of sugar-sweetened soft drinks increases the risk of pancreatic cancer. We examined the relation between consumption of sugar-sweetened soft drinks and the development of pancreatic cancer in the Nurses' Health Study and the Health Professionals Follow-up Study. Among 88,794 women and 49,364 men without cancer at baseline, we documented 379 cases of pancreatic cancer during up to 20 years of follow-up. Soft drink consumption was first assessed at baseline (1980 for the women, 1986 for the men) and updated periodically thereafter. Compared with participants who largely abstained from sugar-sweetened soft drinks, those who consumed more than three sugar-sweetened soft drinks weekly experienced overall a multivariate relative risk (RR) of pancreatic cancer of 1.13 [95% confidence interval (95% CI), 0.81-1.58; P for trend = 0.47]. Women in the highest category of sugar-sweetened soft drink intake did experience a significant increase in risk (RR, 1.57; 95% CI, 1.02-2.41; P for trend = 0.05), whereas there was no association between sweetened soft drink intake and pancreatic cancer among men. Among women, the risk associated with higher sugar-sweetened soft drink was limited to those with elevated body mass index (>25 kg/m(2); RR, 1.89; 95% CI, 0.96-3.72) or with low physical activity (RR, 2.02; 95% CI, 1.06-3.85). In contrast, consumption of diet soft drinks was not associated with an elevated pancreatic cancer risk in either cohort. Although soft drink consumption did not influence pancreatic cancer risk among men, consumption of sugar-sweetened soft drinks may be associated with a modest but significant increase in risk among women who have an underlying degree of insulin resistance.


Ghosts and artifacts in Fourier-transform spectrometry.
Ghosts in Fourier-transform spectrometry are important for three reasons: they can give rise to spurious coincidences of frequency differences in spectral analysis, distort the phase correction, and set a limit to the attainable signal-to-noise ratio. The various types of ghost, originating from amplitude modulation, phase modulation, and intermodulation, are described and discussed, together with some hardware and software artifacts. Recipes are given for identifying these features and, where possible, avoiding harmful effects from them.


Use of web mining in studying innovation.
As enterprises expand and post increasing information about their business activities on their websites, website data promises to be a valuable source for investigating innovation. This article examines the practicalities and effectiveness of web mining as a research method for innovation studies. We use web mining to explore the R&D activities of 296 UK-based green goods small and mid-size enterprises. We find that website data offers additional insights when compared with other traditional unobtrusive research methods, such as patent and publication analysis. We examine the strengths and limitations of enterprise innovation web mining in terms of a wide range of data quality dimensions, including accuracy, completeness, currency, quantity, flexibility and accessibility. We observe that far more companies in our sample report undertaking R&D activities on their web sites than would be suggested by looking only at conventional data sources. While traditional methods offer information about the early phases of R&D and invention through publications and patents, web mining offers insights that are more downstream in the innovation process. Handling website data is not as easy as alternative data sources, and care needs to be taken in executing search strategies. Website information is also self-reported and companies may vary in their motivations for posting (or not posting) information about their activities on websites. Nonetheless, we find that web mining is a significant and useful complement to current methods, as well as offering novel insights not easily obtained from other unobtrusive sources.


The reliability of MinimaxX accelerometers for measuring physical activity in Australian football.
To assess the reliability of triaxial accelerometers as a measure of physical activity in team sports. Eight accelerometers (MinimaxX 2.0, Catapult, Australia) were attached to a hydraulic universal testing machine (Instron 8501) and oscillated over two protocols (0.5 g and 3.0 g) to assess within- and between device reliability. A static assessment was also conducted. Secondly, 10 players were instrumented with two accelerometers during Australian football matches. The vector magnitude was calculated, expressed as Player load and assessed for reliability using typical error (TE) ± 90% confidence intervals (CI), and expressed as a coefficient of variation (CV%). The smallest worthwhile difference (SWD) in Player load was calculated to determine if the device was capable of detecting differences in physical activity. Laboratory: Within- (Dynamic: CV 0.91 to 1.05%; Static: CV 1.01%) and between-device (Dynamic: CV 1.02 to 1.04%; Static: CV 1.10%) reliability was acceptable across each test. Field: The between-device reliability of accelerometers during Australian football matches was also acceptable (CV 1.9%). The SWD was 5.88%. The reliability of the MinimaxX accelerometer is acceptable both within and between devices under controlled laboratory conditions, and between devices during field testing. MinimaxX accelerometers can be confidently utilized as a reliable tool to measure physical activity in team sports across multiple players and repeated bouts of activity. The noise (CV%) of Player load was lower than the signal (SWD), suggesting that accelerometers can detect changes or differences in physical activity during Australian football.


Androgens and eye movements in women and men during a test of mental rotation ability.
Eye movements were monitored in 16 women and 20 men during completion of a standard diagram-based test of mental rotation ability to provide measures of cognitive function not requiring conscious, decisional processes. Overall, women and men allocated visual attention during task performance in very similar, systematic ways. However, consistent with previous suggestions that sex differences in attentional processes during completion of the mental rotation task may exist, eye movements in men compared to women indicated greater discrimination and longer processing of correct alternatives during task performance. Other findings suggested that androgens may enhance cognitive processes that are recruited differentially by women and men as a function of the task. Specifically, smaller (i.e., more masculine) digit ratios were associated with men's shorter fixations on distracters, suggesting that perinatal androgen action may influence brain systems that facilitate the identification of relevant task stimuli. In women, higher circulating testosterone levels appeared to contribute to more general processes engaged during task performance, for example higher levels of visual persistence. It is possible that variability in the relative contribution of such hormone sensitive cognitive processes to accuracy scores as a function of different sample characteristics or assessment methods may partially account for the inconsistent findings of previous research on hormonal factors in mental rotation ability.


Neuromorphic walking gait control.
We present a neuromorphic pattern generator for controlling the walking gaits of four-legged robots which is inspired by central pattern generators found in the nervous system and which is implemented as a very large scale integrated (VLSI) chip. The chip contains oscillator circuits that mimic the output of motor neurons in a strongly simplified way. We show that four coupled oscillators can produce rhythmic patterns with phase relationships that are appropriate to generate all four-legged animal walking gaits. These phase relationships together with frequency and duty cycle of the oscillators determine the walking behavior of a robot driven by the chip, and they depend on a small set of stationary bias voltages. We give analytic expressions for these dependencies. This chip reduces the complex, dynamic inter-leg control problem associated with walking gait generation to the problem of setting a few stationary parameters. It provides a compact and low power solution for walking gait control in robots.


Requirements and standards facilitating quality improvement for reporting systems in gastrointestinal endoscopy: European Society of Gastrointestinal Endoscopy (ESGE) Position Statement.
To develop standards for high quality in gastrointestinal (GI) endoscopy, the European Society of Gastrointestinal Endoscopy (ESGE) has established the ESGE Quality Improvement Committee. A prerequisite for quality assurance and improvement for all GI endoscopy procedures is state-of-the-art integrated digital reporting systems for standardized documentation of the procedures. The current paper describes the ESGE's viewpoints on the requirements for high-quality endoscopy reporting systems in GI endoscopy. Recommendations 1 Endoscopy reporting systems must be electronic. 2 Endoscopy reporting systems should be integrated into hospitals' patient record systems. 3 Endoscopy reporting systems should include patient identifiers to facilitate data linkage to other data sources. 4 Endoscopy reporting systems shall restrict the use of free-text entry to a minimum, and be based mainly on structured data entry. 5 Separate entry of data for quality or research purposes is discouraged. Automatic data transfer for quality and research purposes must be facilitated. 6 Double entry of data by the endoscopist or associate personnel is discouraged. Available data from outside sources (administrative or medical) must be made available automatically. 7 Endoscopy reporting systems shall facilitate the inclusion of information on histopathology of detected lesions, patient satisfaction, adverse events, and surveillance recommendations. 8 Endoscopy reporting systems must facilitate easy data retrieval at any time in a universally compatible format. 9 Endoscopy reporting systems must include data fields for key performance indicators as defined by quality improvement committees. 10 Endoscopy reporting systems must facilitate changes in indicators and data entry fields as required by professional organizations.


Single dose oral dexamethasone versus multi-dose prednisolone in the treatment of acute exacerbations of asthma in children who attend the emergency department: study protocol for a randomized controlled trial.
Asthma is a major cause of pediatric morbidity and mortality. In acute exacerbations of asthma, corticosteroids reduce relapses, subsequent hospital admission and the need for ß₂-agonist therapy. Prednisolone is relatively short-acting with a half-life of 12 to 36 hours, thereby requiring daily dosing. Prolonged treatment course, vomiting and a bitter taste may reduce patient compliance with prednisolone. Dexamethasone is a long-acting corticosteroid with a half-life of 36 to 72 hours. It is used frequently in children with croup and bacterial meningitis, and is well absorbed orally. The purpose of this trial is to examine whether a single dose of oral dexamethasone (0.3 mg/kg) is clinically non-inferior to prednisolone (1 mg/kg/day for three days) in the treatment of exacerbations of asthma in children who attend the Emergency Department. This is a randomized, non-inferiority, open-label clinical trial. After informed consent with or without assent, patients will be randomized to either oral dexamethasone 0.3 mg/kg stat or prednisolone 1 mg/kg/day for three days. The primary outcome measure is the comparison between the Pediatric Respiratory Assessment Measure (PRAM) across both groups on Day 4. The PRAM score, a validated, responsive and reliable tool to determine asthma severity in children aged 2 to 16 years, will be performed by a clinician blinded to treatment allocation. Secondary outcomes include relapse, hospital admission and requirement for further steroid therapy. Data will be analyzed on an intention-to-treat and a per protocol basis. With a sample size of 232 subjects (105 in each group with an estimated 10% loss to follow-up), we will be able to reject the null hypothesis - that the population means of the experimental and control groups are equal with a probability (power) of 0.9. The Type I error probability associated with this test (of the null hypothesis) is 0.05. This clinical trial may provide evidence that a shorter steroid course using dexamethasone can be used in the treatment of acute pediatric asthma, thus eliminating the issue of compliance to treatment. ISRCTN26944158 and EudraCT Number 2010-022001-18.


Outcome of intracerebral hemorrhage associated with different oral anticoagulants.
In an international collaborative multicenter pooled analysis, we compared mortality, functional outcome, intracerebral hemorrhage (ICH) volume, and hematoma expansion (HE) between non-vitamin K antagonist oral anticoagulation-related ICH (NOAC-ICH) and vitamin K antagonist-associated ICH (VKA-ICH). We compared all-cause mortality within 90 days for NOAC-ICH and VKA-ICH using a Cox proportional hazards model adjusted for age; sex; baseline Glasgow Coma Scale score, ICH location, and log volume; intraventricular hemorrhage volume; and intracranial surgery. We addressed heterogeneity using a shared frailty term. Good functional outcome was defined as discharge modified Rankin Scale score ≤2 and investigated in multivariable logistic regression. ICH volume was measured by ABC/2 or a semiautomated planimetric method. HE was defined as an ICH volume increase >33% or >6 mL from baseline within 72 hours. We included 500 patients (97 NOAC-ICH and 403 VKA-ICH). Median baseline ICH volume was 14.4 mL (interquartile range [IQR] 3.6-38.4) for NOAC-ICH vs 10.6 mL (IQR 4.0-27.9) for VKA-ICH (p = 0.78). We did not find any difference between NOAC-ICH and VKA-ICH for all-cause mortality within 90 days (33% for NOAC-ICH vs 31% for VKA-ICH [p = 0.64]; adjusted Cox hazard ratio (for NOAC-ICH vs VKA-ICH) 0.93 [95% confidence interval (CI) 0.52-1.64] [p = 0.79]), the rate of HE (NOAC-ICH n = 29/48 [40%] vs VKA-ICH n = 93/140 [34%] [p = 0.45]), or functional outcome at hospital discharge (NOAC-ICH vs VKA-ICH odds ratio 0.47; 95% CI 0.18-1.19 [p = 0.11]). In our international collaborative multicenter pooled analysis, baseline ICH volume, hematoma expansion, 90-day mortality, and functional outcome were similar following NOAC-ICH and VKA-ICH.


Plasma tau, neurofilament light chain and amyloid-β levels and risk of dementia; a population-based cohort study.
CSF biomarkers, including total-tau, neurofilament light chain (NfL) and amyloid-β, are increasingly being used to define and stage Alzheimer's disease. These biomarkers can be measured more quickly and less invasively in plasma and may provide important information for early diagnosis of Alzheimer's disease. We used stored plasma samples and clinical data obtained from 4444 non-demented participants in the Rotterdam study at baseline (between 2002 and 2005) and during follow-up until January 2016. Plasma concentrations of total-tau, NfL, amyloid-β40 and amyloid-β42 were measured using the Simoa NF-light® and N3PA assays. Associations between biomarker plasma levels and incident all-cause and Alzheimer's disease dementia during follow-up were assessed using Cox proportional-hazard regression models adjusted for age, sex, education, cardiovascular risk factors and APOE ε4 status. Moreover, biomarker plasma levels and rates of change over time of participants who developed Alzheimer's disease dementia during follow-up were compared with age and sex-matched dementia-free control subjects. During up to 14 years follow-up, 549 participants developed dementia, including 374 cases with Alzheimer's disease dementia. A log2 higher baseline amyloid-β42 plasma level was associated with a lower risk of developing all-cause or Alzheimer's disease dementia, adjusted hazard ratio (HR) 0.61 [95% confidence interval (CI), 0.47-0.78; P < 0.0001] and 0.59 (95% CI, 0.43-0.79; P = 0.0006), respectively. Conversely, a log2 higher baseline plasma NfL level was associated with a higher risk of all-cause dementia [adjusted HR 1.59 (95% CI, 1.38-1.83); P < 0.0001] or Alzheimer's disease [adjusted HR 1.50 (95% CI, 1.26-1.78); P < 0.0001]. Combining the lowest quartile group of amyloid-β42 with the highest of NfL resulted in a stronger association with all-cause dementia [adjusted HR 9.5 (95% CI, 2.3-40.4); P < 0.002] and with Alzheimer's disease [adjusted HR 15.7 (95% CI, 2.1-117.4); P < 0.0001], compared to the highest quartile group of amyloid-β42 and lowest of NfL. Total-tau and amyloid-β40 levels were not associated with all-cause or Alzheimer's disease dementia risk. Trajectory analyses of biomarkers revealed that mean NfL plasma levels increased 3.4 times faster in participants who developed Alzheimer's disease compared to those who remained dementia-free (P < 0.0001), plasma values for cases diverged from controls 9.6 years before Alzheimer's disease diagnosis. Amyloid-β42 levels began to decrease in Alzheimer's disease cases a few years before diagnosis, although the decline did not reach significance compared to dementia-free participants. In conclusion, our study shows that low amyloid-β42 and high NfL plasma levels are each independently and in combination strongly associated with risk of all-cause and Alzheimer's disease dementia. These data indicate that plasma NfL and amyloid-β42 levels can be used to assess the risk of developing dementia in a non-demented population. Plasma NfL levels, although not specific, may also be useful in monitoring progression of Alzheimer's disease dementia.


DMD genotype correlations from the Duchenne Registry: Endogenous exon skipping is a factor in prolonged ambulation for individuals with a defined mutation subtype.
Antisense oligonucleotide (AON)-mediated exon skipping is an emerging therapeutic for individuals with Duchenne muscular dystrophy (DMD). Skipping of exons adjacent to common exon deletions in DMD using AONs can produce in-frame transcripts and functional protein. Targeted skipping of DMD exons 8, 44, 45, 50, 51, 52, 53, and 55 is predicted to benefit 47% of affected individuals. We observed a correlation between mutation subgroups and age at loss of ambulation in the Duchenne Registry, a large database of phenotypic and genetic data for DMD (N = 765). Males amenable to exon 44 (N = 74) and exon 8 skipping (N = 18) showed prolonged ambulation compared to other exon skip groups and nonsense mutations (P = 0.035 and P < 0.01, respectively). In particular, exon 45 deletions were associated with prolonged age at loss of ambulation relative to the rest of the exon 44 skip amenable cohort and other DMD mutations. Exon 3-7 deletions also showed prolonged ambulation relative to all other exon 8 skippable mutations. Cultured myotubes from DMD patients with deletions of exons 3-7 or exon 45 showed higher endogenous skipping than other mutations, providing a potential biological rationale for our observations. These results highlight the utility of aggregating phenotypic and genotypic data for rare pediatric diseases to reveal progression differences, identify potentially confounding factors, and probe molecular mechanisms that may affect disease severity.


Alternative NF-κB Isoforms in the Drosophila Neuromuscular Junction and Brain.
The Drosophila NF-κB protein Dorsal is expressed at the larval neuromuscular junction, where its expression appears unrelated to known Dorsal functions in embryonic patterning and innate immunity. Using confocal microscopy with domain-specific antisera, we demonstrate that larval muscle expresses only the B isoform of Dorsal, which arises by intron retention. We find that Dorsal B interacts with and stabilizes Cactus at the neuromuscular junction, but exhibits Cactus independent localization and an absence of detectable nuclear translocation. We further find that the Dorsal-related immune factor Dif encodes a B isoform, reflecting a conservation of B domains across a range of insect NF-κB proteins. Carrying out mutagenesis of the Dif locus via a site-specific recombineering approach, we demonstrate that Dif B is the major, if not sole, Dif isoform in the mushroom bodies of the larval brain. The Dorsal and Dif B isoforms thus share a specific association with nervous system tissues as well as an alternative protein structure.


Intranasal administration of human MSC for ischemic brain injury in the mouse: in vitro and in vivo neuroregenerative functions.
Intranasal treatment with C57BL/6 MSCs reduces lesion volume and improves motor and cognitive behavior in the neonatal hypoxic-ischemic (HI) mouse model. In this study, we investigated the potential of human MSCs (hMSCs) to treat HI brain injury in the neonatal mouse. Assessing the regenerative capacity of hMSCs is crucial for translation of our knowledge to the clinic. We determined the neuroregenerative potential of hMSCs in vitro and in vivo by intranasal administration 10 d post-HI in neonatal mice. HI was induced in P9 mouse pups. 1×10(6) or 2×10(6) hMSCs were administered intranasally 10 d post-HI. Motor behavior and lesion volume were measured 28 d post-HI. The in vitro capacity of hMSCs to induce differentiation of mouse neural stem cell (mNSC) was determined using a transwell co-culture differentiation assay. To determine which chemotactic factors may play a role in mediating migration of MSCs to the lesion, we performed a PCR array on 84 chemotactic factors 10 days following sham-operation, and at 10 and 17 days post-HI. Our results show that 2×10(6) hMSCs decrease lesion volume, improve motor behavior, and reduce scar formation and microglia activity. Moreover, we demonstrate that the differentiation assay reflects the neuroregenerative potential of hMSCs in vivo, as hMSCs induce mNSCs to differentiate into neurons in vitro. We also provide evidence that the chemotactic factor CXCL10 may play an important role in hMSC migration to the lesion site. This is suggested by our finding that CXCL10 is significantly upregulated at 10 days following HI, but not at 17 days after HI, a time when MSCs no longer reach the lesion when given intranasally. The results described in this work also tempt us to contemplate hMSCs not only as a potential treatment option for neonatal encephalopathy, but also for a plethora of degenerative and traumatic injuries of the nervous system.


Relationships between cell division, expression of growth factors and microcirculation in the thyroids of Tg-A2aR transgenic mice and patients with Graves' disease.
Tissue heterogeneity and nodule formation are hallmarks of thyroid growth. This is accounted for by the clonality theory that acknowledges different individual cellular abilities to respond to trophic stimuli. In order to test the hypothesis that functional and mitotic properties of thyrocytes could be influenced by paracrine interactions with neighbour endothelial cells, studies were conducted in both mouse and human goitre models. In the first part of the study, homogenous goitres in C57 black mice were compared with heterogeneous goitres in transgenic hyperthyroid mice expressing the A2 adenosine receptor (Tg-A2aR). The second part of the study concentrated on comparing human thyroid tIssue of control individuals and of patients with Graves' disease. The rate of cell division was evaluated by immunohistochemical detection of cells positive for proliferating cell nuclear antigen (PCNA). Their spatial distribution was then correlated with immunohistochemical cellular expression of growth- and vasoactive-related factors (fibroblast growth factor-2, transforming growth factor-beta, endothelin-1, vascular endothelial growth factor, nitric oxide synthase III), and with microcirculation expansion. Observations were made on digitalised images of histological serial sections. The nearest-neighbour method was used to distinguish between random or clustered distribution. PCNA-positive cells were both randomly and uniformly distributed in homogenous goitres from C57 black mice, and were clustered in tIssue areas identified as papillary and hyperplastic zones in heterogeneous goitres from Tg-A2aR mice. However, they were absent in the so-called compact cellular zones featuring resting cells. Moreover, whereas papillary and hyperplastic zones were highly vascularised, compact zones were nearly free of microvessels. Spatial distribution of dividing cells was positively correlated with the expression of growth-related factors. A similar pattern was observed in the thyroids of patients with Graves' disease. In accordance with the recent demonstration of the presence of angiofollicular units in the thyroid, these data strongly support the hypothesis that functional and mitotic properties of each single thyrocyte, likely to be responsible for growth heterogeneity of hyperplastic glands, may be adjusted at tIssue level by specific interactions with neighbour endothelial cells that, in turn, could alter the mitotic rate of thyrocytes through paracrine signals.


Stability of food neophobia from infancy through early childhood.
The purpose of the present study was to examine whether rejection of novel foods during infancy predicted child behavioral and parent-reported neophobia at 4.5 years of age. Data for the present study were drawn from a longitudinal study following individuals (n = 82) from infancy through early childhood. At 6 and 12 months of age, the infants tasted a novel food (green beans, hummus, or cottage cheese) and their reactions were coded for rejection of the food (i.e. crying, force outs, or refusals). The children returned to the laboratory at 4.5 years of age and participated in a behavioral neophobia task where they were offered three novel foods (lychee, nori, and haw jelly) and the number of novel foods they tasted was recorded. Mothers also reported their own and their children's levels of food neophobia. Regression analyses revealed that rejection of novel foods at 6 months interacted with maternal neophobia to predict parent-rated child neophobia. Infants who exhibited low levels of rejection at 6 months showed higher levels of parent-rated neophobia when their mothers also showed high compared to low levels of neophobia. At 12 months of age, however, infants who exhibited high levels of rejection tended to have high levels of parent-rated neophobia regardless of their mothers' levels of neophobia. These results provide preliminary evidence that rejection of novel foods during infancy does predict neophobia during early childhood, but the results vary depending on when rejection of new foods is measured.


Health-related quality of life in the Cambridge City over-75s Cohort (CC75C): development of a dementia-specific scale and descriptive analyses.
The assessment of Health Related Quality of Life (HRQL) is important in people with dementia as it could influence their care and support plan. Many studies on dementia do not specifically set out to measure dementia-specific HRQL but do include related items. The aim of this study is to explore the distribution of HRQL by functional and socio-demographic variables in a population-based setting. Domains of DEMQOL's conceptual framework were mapped in the Cambridge City over 75's Cohort (CC75C) Study. HRQL was estimated in 110 participants aged 80+ years with a confirmed diagnosis of dementia with mild/moderate severity. Acceptability (missing values and normality of the total score), internal consistency (Cronbach's alpha), convergent, discriminant and known group differences validity (Spearman correlations, Wilcoxon Mann-Whitney and Kruskal-Wallis tests) were assessed. The distribution of HRQL by socio-demographic and functional descriptors was explored. The HRQL score ranged from 0 to 16 and showed an internal consistency Alpha of 0.74. Validity of the instrument was found to be acceptable. Men had higher HRQL than women. Marital status had a greater effect on HRQL for men than it did for women. The HRQL of those with good self-reported health was higher than those with fair/poor self-reported health. HRQL was not associated with dementia severity. To our knowledge this is the first study to examine the distribution of dementia-specific HRQL in a population sample of the very old. We have mapped an existing conceptual framework of dementia specific HRQL onto an existing study and demonstrated the feasibility of this approach. Findings in this study suggest that whereas there is big emphasis in dementia severity, characteristics such as gender should be taken into account when assessing and implementing programmes to improve HRQL.


Can Burkitt's Lymphoma and Hodgkin's Lymphoma occur in siblings simultaneously?
Familial clustering of Hodgkin lymphoma (HL) and increased risk of developing disease among the siblings has been reported earlier. Usually familial lymphoma in sibling pairs occurs in the pairs of either non-Hodgkin lymphoma or HL. In the familial HL, same type of human leukocyte antigens (HLA) is responsible in the affected family members. There are also some studies stating "Killer cell immunoglobulin like receptor (KIR)" genotypes can be important in the etiology of familial HL. Here we report two siblings; one with Non-Hodgkin and the other with Hodgkin lymphoma which showed Epstein-Barr virus encoded small RNAs positivity in the tumor tissues. We have also found that their HLA genotypes are same with each other. In addition, we have discussed familial lymphoma pathogenesis and HLA haplotypes.


Lymph node dissection at the time of radical nephrectomy for high-risk clear cell renal cell carcinoma: indications and recommendations for surgical templates.
Observational studies suggest a proportion of patients with lymph node metastases will benefit from lymph node dissection (LND) at the time of nephrectomy for clear cell renal cell carcinoma (RCC). Our aim was to report the performance of five previously identified high-risk pathologic features assessed by intraoperative examination on prediction of lymph node metastases and propose a template for LND based on locations of lymph node involvement. The study included a historical cohort of consecutive patients from a single institution who received LND in conjunction with nephrectomy for high-risk clear cell RCC between 2002 and 2006. All patients underwent nephrectomy and LND. Patients were considered high risk for nodal metastasis if two or more of the following features were identified during intraoperative pathologic assessment of the primary tumor: nuclear grade 3 or 4, sarcomatoid component, tumor size ≥10 cm, tumor stage pT3 or pT4, or coagulative tumor necrosis. Based on these features, LND was performed at the time of nephrectomy, and the numbers and sites of regional lymph node metastasis were recorded for each patient. Of the 169 high-risk patients, 64 (38%) had lymph node metastases. All patients with nodal metastases had nodal involvement within the primary lymphatic sites of each kidney prior to involvement of the nodes overlying the contralateral great vessel. A limitation of the study is the lack of a standardized LND performed throughout the study period. Pathologic features of renal tumors are associated with the risk of regional lymph node metastases and lymph node metastases that appear to progress though the primary lymphatic drainage of each kidney. Based on these findings we recommend that when performing LND the lymph nodes from the ipsilateral great vessel and the interaortocaval region be removed from the crus of the diaphragm to the common iliac artery.


Green tea leaf extract improves lipid and glucose homeostasis in a fructose-fed insulin-resistant hamster model.
The present study evaluated the effect of green tea (Camellia sinensis L.) leaf extract on triglyceride and glucose homeostasis in a fructose-fed hypertriglyceridemic, insulin-resistant hamster model. There was a significant decrease in plasma triglyceride levels following supplementation of the green tea epigallocatechin gallate-enriched extract (42% at 150 mg/(kg day) to 62% at 300 mg/(kg day) for 4 weeks). Compared to baseline, the fructose control group at the end of the study showed elevated serum insulin and apolipoprotein B levels, and decreased serum adiponectin levels. The fructose/green tea extract group showed a reversal in all of these metabolic defects, including an improvement in glucose levels during a glucose tolerance test. Triglyceride content was also examined in various tissues and compared to the control fructose group; supplementation of the green tea extract (300 mg/kg) reduced triglyceride content in liver and heart tissues. There was molecular evidence of improved lipid and glucose homeostasis based on peroxisome proliferator-activated receptor (PPAR) protein expression. Compared to the control fructose group, supplementation of the green tea extract (300 mg/kg) significantly increased PPARalpha and PPARgamma protein expression. In summary, the data suggest that intake of the green tea extract ameliorated the fructose-induced hypertriglyceridemia and the insulin-resistant state in part through PPAR.