Assessing causality between childhood adiposity and early puberty: A bidirectional Mendelian randomization and longitudinal study.
Obesity and early puberty have been reported to be mutually causative. We investigated the causal relationship between adiposity and early puberty by performing bidirectional Mendelian randomization (MR) and longitudinal data analyses. We used information from the Taiwan Children Health Study (3109 adolescents aged 11-12 years) with 17 body mass index (BMI)- and 10 puberty-related single-nucleotide polymorphisms (SNPs) to produce genetic instrumental variables (IVs). The two-stage least squares (2SLS) method, MR sensitivity analysis, and survival analysis were used to explore and confirm causality. Regression estimates from IVs revealed that significantly increased association of BMI with early puberty was noted (coefficients: 0.13, 0.10, and 0.09; 95% CI: 0.07-0.19, 0.02-0.19, and 0.02-0.16 for all participants, male adolescents, and female adolescents, respectively). Genetic IVs for puberty were not associated with BMI. MR sensitivity and two-sample MR analyses produced similar results. Longitudinal analysis results revealed that prepubertal overweight and obesity could predict early onset of puberty. However, after excluding children with a history of overweight and obesity at the age of 7-12 years, early puberty was not found to trigger new-onset of overweight and obesity at the age of 18 years in either sex. Higher adiposity may lead to early puberty. However, the causal effects of early puberty on adiposity accumulation were not supported by our data. Targeted interventions to reduce childhood obesity are strongly recommended to prevent obesity-related comorbidities, as well as early puberty onset.


Multi-frame super-resolution reconstruction of small moving objects.
Multiframe super-resolution (SR) reconstruction of small moving objects against a cluttered background is difficult for two reasons: a small object consists completely of "mixed" boundary pixels and the background contribution changes from frame-to-frame. We present a solution to this problem that greatly improves recognition of small moving objects under the assumption of a simple linear motion model in the real-world. The presented method not only explicitly models the image acquisition system, but also the space-time variant fore- and background contributions to the "mixed" pixels. The latter is due to a changing local background as a result of the apparent motion. The method simultaneously estimates a subpixel precise polygon boundary as well as a high-resolution (HR) intensity description of a small moving object subject to a modified total variation constraint. Experiments on simulated and real-world data show excellent performance of the proposed multiframe SR reconstruction method.


Down syndrome critical region-1 is a transcriptional target of nuclear factor of activated T cells-c1 within the endocardium during heart development.
Patients with Down syndrome have characteristic heart valve lesions resulting from endocardial cushion defects. The Down syndrome critical region 1 (DSCR1) gene, identified at the conserved trisomic 21 region in those patients, encodes a calcineurin inhibitor that inactivates nuclear factor of activated T cells (NFATc) activity. Here, we identify a regulatory sequence in the promoter region of human DSCR1 that dictates specific expression of a reporter gene in the endocardium, defined by the temporal and spatial expression of Nfatc1 during heart valve development. Activation of this evolutionally conserved DSCR1 regulatory sequence requires calcineurin and NFATc1 signaling in the endocardium. NFATc1 proteins bind to the regulatory sequence and trigger its enhancer activity. NFATc1 is sufficient to induce the expression of Dscr1 in cells that normally have undetectable or minimal NFATc1 or DSCR1. Pharmacologic inhibition of calcineurin or genetic Nfatc1 null mutation in mice abolishes the endocardial activity of this DSCR1 enhancer. Furthermore, in mice lacking endocardial NFATc1, the endogenous Dscr1 expression is specifically inhibited in the endocardium but not in the myocardium. Thus, our studies indicate that the DSCR1 gene is a direct transcriptional target of NFATc1 proteins within the endocardium during a critical window of heart valve formation.


Comparison of nebulised magnesium sulphate and salbutamol combined with salbutamol alone in the treatment of acute bronchial asthma: a randomised study.
To test the hypothesis that combined administration of multiple doses of nebulised salbutamol and magnesium sulphate provides additional benefit compared with salbutamol alone in adult patients with acute asthma. Randomised, double blind, prospective study. A total of 100 patients presenting to an emergency department with an acute attack of bronchial asthma were randomised to two groups: nebulisation with a combination of salbutamol and magnesium sulphate (group A) and nebulisation with salbutamol only (group B). Both groups received nebulisation thrice at intervals of 20 minutes. Salbutamol and magnesium sulphate were administered in doses of 0.5 mg and 500 mg, respectively, and the solutions were made isotonic to plasma osmolality. Pulse rate, blood pressure, and peak expiratory flow rate (PEFR) were measured at baseline and at 15, 60, 75, and 120 minutes. Serum magnesium levels and blood gases were measured at 0 and 120 minutes in both groups. All patients had either acute severe or life threatening asthma. The baseline characteristics were comparable in the two groups. Both groups showed significant rise in PEFR at all time intervals, however, there was no significant difference between the groups in rise in PEFR at any time point. Serum magnesium levels remained within normal limits, and there was no difference in requirement of additional medication during the study or hospital admission rates in both groups. No significant side effects were noted. This study suggests that there is no therapeutic benefit of adding magnesium sulphate to salbutamol nebulisation in the treatment of patients with acute severe or life threatening asthma.


Evaporation-Driven Micromixing in Sessile Droplets for Miniaturized Absorbance-Based Colorimetry.
We demonstrate the use of an evaporating, sessile droplet on a nonwetting substrate as a miniature micromixing device to conduct sample-dye reactions for absorbance-based colorimetry. The nonwetting substrate supports buoyancy-induced mixing inside the droplet for rapid completion of the measurement. The Bradford assay is used as a proof of concept, where a protein-containing sample is reacted with a reagent dye to measure the protein concentration. Viability of absorbance measurement through the droplet is first established using droplets in which the reactants are mixed prior to their deposition onto the substrate. In a second set of experiments involving in situ mixing, the reagent is directly added to a sessile droplet of the protein-containing sample, allowing the reactants to mix while the absorbance is being measured. Interplay between buoyancy-induced mixing, protein-reagent reaction, and protein adsorption onto the substrate leads to a complex temporal absorbance measurement signal. Videos corresponding to the signal data show that each of these mechanisms dominates during different phases of droplet evolution, causing a signal pattern containing peaks and valleys having a strong monotonic trend with the protein concentration. Overall, the second absorbance peak at which the reaction nears completion is the most sensitive to sample concentration. Heating of the substrate is demonstrated to dramatically speed up the mixing process. These protein concentration measurements, obtained with a simpler system and low reactant volumes, demonstrate that this droplet micromixing concept is a viable alternative to microtiter plates for colorimetric applications.


SERS-based immunoassay of tumor marker VEGF using DNA aptamers and silica-encapsulated hollow gold nanospheres.
A novel SERS-based sandwich immunoassay using DNA aptamers, silica-encapsulated hollow gold nanospheres (SEHGNs) and a gold-patterned microarray was developed for sensitive detection of VEGF (vascular endothelial growth factor) angiogenesis protein markers. Here, a DNA aptamer conjugated to SEHGN was used as a highly reproducible SERS-encoding nanoprobe, and a hybrid microarray including hydrophilic gold wells and other hydrophobic areas was used as a SERS substrate. Target specific DNA aptamers that fold into a G-quadruplex structure were used as a target recognition unit instead of VEGF antibodies. The detection sensitivity was increased by 2 or 3 orders of magnitude over the conventional ELISA method. In particular, the dynamic concentration range was 3 or 4 orders of magnitude greater than that of conventional ELISA. The results demonstrate that this sensing strategy using DNA aptamers is a powerful platform for the design of novel immune-sensors with high performance. In particular, SERS-based detection using SEHGNs provides great promise for highly sensitive biomarker sensing with unprecedented advantages.


Expanded HTA: Enhancing Fairness and Legitimacy.
All societies face the need to make judgments about what interventions (both public health and personal medical) to provide to their populations under reasonable resource constraints. Their decisions should be informed by good evidence and arguments from health technology assessment (HTA). But if HTA restricts itself to evaluations of safety, efficacy, and cost-effectiveness, it risks being viewed as insufficient to guide health decision-makers; if it addresses other issues, such as budget impact, equity, and financial protection, it may be accused of overreaching. But the risk of overreaching can be reduced by embedding HTA in a fair, deliberative process that meets the conditions required by accountability for reasonableness.


Antidiabetic effect of honey feeding in noise induced hyperglycemic rat: involvement of oxidative stress.
In this study the effect of oral administration of honey on serum glucose, lipids, stress oxidative markers, and morphology of langerhans islets in noise induced hyperglycemic rats was investigated. Male Wistar rats were divided into control, hyperglycemic, honey treated control, and honey treated hyperglycemic groups. For induction of hyperglycemia, noise stress was used. Serum glucose, triglyceride (TG), total cholesterol, low density lipoprotein (LDL), and high density lipoprotein (HDL)-cholesterol levels were determined before the study and at 4(th) and 8(th) weeks after the study. Markers of oxidative stress in brain were also measured. Morphology of langerhans islets in four groups was evaluated using Gomori staining method. Treatment of noise induced hyperglycemic rats with honey produced a hypoglycemic effect and appropriate changes regarding serum lipids in treated diabetic group at 4(th) and 8(th) weeks as compared to the control group. Meanwhile, honey treatment significantly ameliorated the increased malondialdehyde (MDA) content and reduced the activity of superoxide dismutase (SOD) in brain. Histology of langerhans islets in hyperglycemic group showed a lower number and granularity of beta cells; honey treatment produced beneficial change in this respect. Oral administration of honey in experimental model of diabetes showed a significant hypoglycemic effect and led to appropriate changes in serum lipid profiles.


Race/ethnic Differences in Post-stroke Depression (PSD): Findings from the Stroke Warning Information and Faster Treatment (SWIFT) Study.
Post-stroke depression (PSD) is common and associated with poor stroke outcomes, but few studies have examined race/ethnic disparities in PSD. Given the paucity of work and inconsistent findings in this important area of research, our study aimed to examine race/ethnic differences in depression in a multi-ethnic cohort of stroke patients. Longitudinal. Prospective trial of a post-stroke educational intervention. 1,193 mild/moderate ischemic stroke/transient ischemic attack (TIA) patients. We used the Center for Epidemiologic Studies Depression (CES-D) Scale to assess subthreshold (CES-D score 8-15) and full (CES-D score ≥ 16) depression at one month ("early") and 12 months ("late") following stroke. Multinomial logistic regression analyses examined the association between race/ethnicity and early and late PSD separately. The prevalence of subthreshold and full PSD was 22.5% and 32.6% in the early period and 22.0% and 27.4% in the late period, respectively. Hispanics had 60% lower odds of early full PSD compared with non-Hispanic Whites after adjusting for other covariates (OR=.4, 95% CI: .2, .8). Race/ethnicity was not significantly associated with late PSD. Hispanic stroke patients had half the odds of PSD in early period compared with Whites, but no difference was found in the later period. Further studies comparing trajectories of PSD between race/ethnic groups may further our understanding of race/ethnic disparities in PSD and help identify effective interventions.


Communication in general practice: differences between European countries.
Based on differences in national health care system characteristics such as the gatekeeping role of GPs (at the macrolevel) and on diverging GP and patient characteristics (at the microlevel), communication may differ between countries. Knowledge of the influence of these characteristics on doctor-patient communication will be important for setting European health care policies. Our objectives were (i) to compare doctor-patient communication in general practice between European countries; and (ii) to investigate the influence of the gatekeeping system and GP and patient characteristics on doctor-patient communication in general practice. Fifteen patients per GP (in total 2825 patients) of 190 GPs in six European countries were included. Participating countries were The Netherlands, Spain, the UK (gatekeeping countries), Belgium, Germany and Switzerland (non-gatekeeping countries). Data were collected by means of patient and GP questionnaires and observation of videotaped consultations, and analysed by one-way and multilevel, multivariate analysis. Differences in communication between countries were found in: affective and instrumental behaviour; biomedical and psychosocial talk; GPs' patient-directed gaze; and consultation length. The study showed that GPs' gatekeeping role (with registered patients) was less important for doctor-patient communication than was expected. Patient characteristics such as gender, age, having psychosocial problems, and familiarity between the doctor and the patient were the most important in explaining differences in communication. The gatekeeping role of GPs is hardly important in explaining doctor-patient communication. The relationship is more complex than expected. Patient and GP characteristics are more important. Cultural factors should be included in future studies.


A review of the surgical treatment options for the obstructive sleep apnea/hypopnea syndrome patient.
Obstructive sleep apnea/hypopnea syndrome (OSAHS) is a medical condition that has received significant attention within the medical community and mainstream media due to its potentially serious physiological consequences and relatively frequent occurrence within the general population. From the military perspective, the impact on individual readiness for deployment, and the potential degradation of performance in critically important military duties, often results in tremendous expenditures of training resources, time, and expertise to replace the military member with a suitable substitute or release of the individual from active duty. This article reviews common surgical techniques for clinical management of OSAHS patients in a presentation format for primary care and sleep medicine specialists, as well as surgeons interested in the philosophies of surgical management of sleep disordered breathing. Presentation of risks and benefits of surgical treatment are discussed in a manner to facilitate communication between patient and health care provider.


The in vivo ISGylome links ISG15 to metabolic pathways and autophagy upon Listeria monocytogenes infection.
ISG15 is an interferon-stimulated, ubiquitin-like protein, with anti-viral and anti-bacterial activity. Here, we map the endogenous in vivo ISGylome in the liver following Listeria monocytogenes infection by combining murine models of reduced or enhanced ISGylation with quantitative proteomics. Our method identifies 930 ISG15 sites in 434 proteins and also detects changes in the host ubiquitylome. The ISGylated targets are enriched in proteins which alter cellular metabolic processes, including upstream modulators of the catabolic and antibacterial pathway of autophagy. Computational analysis of substrate structures reveals that a number of ISG15 modifications occur at catalytic sites or dimerization interfaces of enzymes. Finally, we demonstrate that animals and cells with enhanced ISGylation have increased basal and infection-induced autophagy through the modification of mTOR, WIPI2, AMBRA1, and RAB7. Taken together, these findings ascribe a role of ISGylation to temporally reprogram organismal metabolism following infection through direct modification of a subset of enzymes in the liver.


Design, fabrication and optical characterization of photonic crystal assisted thin film monocrystalline-silicon solar cells.
In this paper, we present the integration of an absorbing photonic crystal within a monocrystalline silicon thin film photovoltaic stack fabricated without epitaxy. Finite difference time domain optical simulations are performed in order to design one- and two-dimensional photonic crystals to assist crystalline silicon solar cells. The simulations show that the 1D and 2D patterned solar cell stacks would have an increased integrated absorption in the crystalline silicon layer would increase of respectively 38% and 50%, when compared to a similar but unpatterned stack, in the whole wavelength range between 300 nm and 1100 nm. In order to fabricate such patterned stacks, we developed an effective set of processes based on laser holographic lithography, reactive ion etching and inductively coupled plasma etching. Optical measurements performed on the patterned stacks highlight the significant absorption increase achieved in the whole wavelength range of interest, as expected by simulation. Moreover, we show that with this design, the angle of incidence has almost no influence on the absorption for angles as high as around 60°.


Age estimation based on aspartic acid racemization in human sclera.
Age estimation based on racemization of aspartic acid residues (AAR) in permanent proteins has been established in forensic medicine for years. While dentine is the tissue of choice for this molecular method of age estimation, teeth are not always available which leads to the need to identify other suitable tissues. We examined the suitability of total tissue samples of human sclera for the estimation of age at death. Sixty-five samples of scleral tissue were analyzed. The samples were hydrolyzed and after derivatization, the extent of aspartic acid racemization was determined by gas chromatography. The degree of AAR increased with age. In samples from younger individuals, the correlation of age and D-aspartic acid content was closer than in samples from older individuals. The age-dependent racemization in total tissue samples proves that permanent or at least long-living proteins are present in scleral tissue. The correlation of AAR in human sclera and age at death is close enough to serve as basis for age estimation. However, the precision of age estimation by this method is lower than that of age estimation based on the analysis of dentine which is due to molecular inhomogeneities of total tissue samples of sclera. Nevertheless, the approach may serve as a valuable alternative or addition in exceptional cases.


Incompetent to Stand Trial, Not Restorable, and Dangerous.
This article focuses on the preferred disposition for an individual charged with a serious crime against another person, adjudicated incompetent to stand trial and not restorable to competence, whose original criminal charges are dismissed without prejudice, and who is regarded by the state as dangerous to the general public. Three current models used today in California, Oregon, and Ohio are described. All three rely on modifications of various aspects of civil commitment law. We then propose a fourth model based on a modified version of the 1989 American Bar Association (ABA) Criminal Justice Mental Health Standards, in which individuals who are found incompetent to stand trial and not restorable to competence and are considered dangerous would be committed under the same special procedures governing the management and treatment of insanity acquittees.


Topographic and soil influences on root productivity of three bioenergy cropping systems.
Successful modeling of the carbon (C) cycle requires empirical data regarding species-specific root responses to edaphic characteristics. We address this need by quantifying annual root production of three bioenergy systems (continuous corn, triticale/sorghum, switchgrass) in response to variation in soil properties across a toposequence within a Midwestern agroecosystem. Using ingrowth cores to measure annual root production, we tested for the effects of topography and 11 soil characteristics on root productivity. Root production significantly differed among cropping systems. Switchgrass root productivity was lowest on the floodplain position, but root productivity of annual crops was not influenced by topography or soil properties. Greater switchgrass root production was associated with high percent sand, which explained 45% of the variation. Percent sand was correlated negatively with soil C and nitrogen and positively with bulk density, indicating this variable is a proxy for multiple important soil properties. Our results suggest that easily measured soil parameters can be used to improve model predictions of root productivity in bioenergy switchgrass, but the edaphic factors we measured were not useful for predicting root productivity in annual crops. These results can improve C cycling modeling efforts by revealing the influence of cropping system and soil properties on root productivity.


Crayfish use of trash versus natural cover in incised, sand-bed streams.
Historic land use changes and subsequent river channelization created deeply incised, unstable stream channels largely devoid of natural cover throughout the Yazoo River basin, Mississippi, USA. Large trash (e.g., televisions, toilets, car parts) dumped in streams provided shelter for some aquatic fauna. To determine whether trash served as a surrogate for natural cover, I examined crayfish use of both cover types. I sampled crayfishes by kick-seining 2 × 1-m plots in three cover classes: trash, natural cover, and no cover. I captured 415 crayfishes from 136 of the 294 plots. Most crayfishes were in natural cover (253), followed by trash (154), and no-cover (8) plots. Trash use varied by crayfish genus and size. Frequencies of all size classes of Procambarus and of the smallest Cambarus were higher in natural cover than trash. Many of the smallest individuals were found in live root mats. As Cambarus and Orconectes grew, they shifted more toward trash, and the largest Orconectes size class was significantly more abundant than expected in trash. Trash served as "artificial reefs," providing cover for crayfishes and other fauna, but functioned differently than the remaining natural cover. The results confirmed that stream substrate did not provide adequate instream cover for crayfishes in the study area and suggested that high-quality natural cover for large crayfishes was in short supply, at least for some species. Land management that provides for abundant, ongoing input and retention of complex cover, such as trees and live roots, to stream channels should be beneficial for crayfish assemblages.


A family-centered educational program to promote independence in pediatric heart transplant recipients.
Characteristic adolescent risk-taking behavior, including nonadherence with prescribed medications, can be life-threatening for transplant recipients. Suggestions for managing nonadherence in teen recipients include providing them and their parents with adequate information about medications, talking with and listening to pediatric recipients about problems with the comprehensive regimen, and encouraging age-appropriate responsibility for maintaining health. The clinical goal of this project was to develop a structured age-appropriate educational program to prepare pediatric transplant recipients and their families for the patient's life as a responsible, independent individual. Our primary research goal was to assess patients' and parents' knowledge about critical aspects of heart transplantation and the treatment regimen with brief questionnaires before and after they received the educational materials from their primary nurse coordinator. This descriptive pre-post test study was done to assess the effectiveness of an innovative family-centered educational program among 20 pediatric heart transplant recipients and their parents at Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center. MAIN OUTCOME MEASURE, RESULTS: Percentage change in children's scores on questionnaires given before and after the educational intervention ranged from -8% to 300% (mean, 64.1%). Percentage change in scores from before to after for parents ranged from -19% to 53.8% (mean, 7.2%).


Non-linear growth in tree ferns, Dicksonia antarctica and Cyathea australis.
Tree ferns are an important structural component of forests in many countries. However, because their regeneration is often unrelated to major disturbances, their age is often difficult to determine. In addition, rates of growth may not be uniform, which further complicates attempts to determine their age. In this study, we measured 5 years of growth of Cyathea australis and Dicksonia antarctica after a large wildfire in 2009 in south-eastern Australia. We found growth rates of these two species were unaffected by aspect and elevation but slope had a minor effect with D. antarctica growing 0.3mm faster for each additional degree of slope. Geographic location influenced growth in both species by up to 12 - 14mm/yr. The most consistent factor influencing growth rate, however, was initial height at the time of the 2009 fire; a finding consistent in both species and all geographic locations. For both tree fern species, individuals that were taller at the commencement of the study had greater overall growth for the duration of the study. This effect did not decrease even among the tallest tree ferns in our study (up to 6 metres tall). Overall, Cyathea australis averaged 73 (± 22)mm/year of growth (± 1SD), with the rate increasing 5mm/yr per metre of additional height. Dicksonia antarctica averaged 33 (± 13)mm/year, increasing by 6mm/yr/m. Growth rates dependent on initial height were unexpected and we discuss possible reasons for this finding. Variable growth rates also suggest that common age estimation methods of dividing height by average growth rate are likely to underestimate the age of short tree ferns, while overestimating the age of tall tree ferns, particularly if they have been subject to a fire.


Microbial regulation in gorgonian corals.
Gorgonian corals possess many novel natural products that could potentially mediate coral-bacterial interactions. Since many bacteria use quorum sensing (QS) signals to facilitate colonization of host organisms, regulation of prokaryotic cell-to-cell communication may represent an important bacterial control mechanism. In the present study, we examined extracts of twelve species of Caribbean gorgonian corals, for mechanisms that regulate microbial colonization, such as antibacterial activity and QS regulatory activity. Ethanol extracts of gorgonians collected from Puerto Rico and the Florida Keys showed a range of both antibacterial and QS activities using a specific Pseudomonas aeruginosa QS reporter, sensitive to long chain AHLs and a short chain N-acylhomoserine lactones (AHL) biosensor, Chromobacterium violaceium. Overall, the gorgonian corals had higher antimicrobial activity against non-marine strains when compared to marine strains. Pseudopterogorgia americana, Pseusopterogorgia acerosa, and Pseudoplexuara flexuosa had the highest QS inhibitory effect. Interestingly, Pseudoplexuara porosa extracts stimulated QS activity with a striking 17-fold increase in signal. The stimulation of QS by P. porosa or other elements of the holobiont may encourage colonization or recruitment of specific microbial species. Overall, these results suggest the presence of novel stimulatory QS, inhibitory QS and bactericidal compounds in gorgonian corals. A better understanding of these compounds may reveal insight into coral-microbial ecology and whether a therapeutic potential exists.


Circulating αKlotho influences phosphate handling by controlling FGF23 production.
The FGF23 coreceptor αKlotho (αKL) is expressed as a membrane-bound protein (mKL) that forms heteromeric complexes with FGF receptors (FGFRs) to initiate intracellular signaling. It also circulates as an endoproteolytic cleavage product of mKL (cKL). Previously, a patient with increased plasma cKL as the result of a translocation [t(9;13)] in the αKLOTHO (KL) gene presented with rickets and a complex endocrine profile, including paradoxically elevated plasma FGF23, despite hypophosphatemia. The goal of this study was to test whether cKL regulates phosphate handling through control of FGF23 expression. To increase cKL levels, mice were treated with an adeno-associated virus producing cKL. The treated groups exhibited dose-dependent hypophosphatemia and hypocalcemia, with markedly elevated FGF23 (38 to 456 fold). The animals also manifested fractures, reduced bone mineral content, expanded growth plates, and severe osteomalacia, with highly increased bone Fgf23 mRNA (>150 fold). cKL activity in vitro was specific for interactions with FGF23 and was FGFR dependent. These results demonstrate that cKL potently stimulates FGF23 production in vivo, which phenocopies the KL translocation patient and metabolic bone syndromes associated with elevated FGF23. These findings have important implications for the regulation of αKL and FGF23 in disorders of phosphate handling and biomineralization.


Clonal rearrangements of immunoglobulin genes and progression to B cell lymphoma in cutaneous lymphoid hyperplasia.
Cutaneous lymphoid hyperplasia (CLH) is a disorder characterized by the development of one or more skin lesions containing dense lymphoid infiltrates that exhibit the histopathologic features of a benign, reactive process. Nevertheless, some cases have been associated with the subsequent development of clinically overt lymphomas. This suggests that monoclonal populations may exist in some cases of CLH and that these cases may represent a subset more likely to evolve into lymphoma. To determine if such a subset of CLH can be distinguished, Southern blot analysis of DNA was used to study the immunogenotypic features of lesions from 14 patients with clinical, histopathologic, and immunopathologic findings characteristic of CLH. Five cases exhibited detectable clonal rearrangements of immunoglobulin genes. Furthermore, one of these five cases evolved into overt diffuse large cell lymphoma of B cell lineage during a 2-year follow-up of recurrent disease at the original cutaneous site. The immunoglobulin gene rearrangements of this lymphoma were identical to those of the prior CLH lesion. There was no evidence of detectable t(14;18) chromosomal translocations or clonal rearrangements of the beta gene of the T cell receptor in any case. It was concluded that CLH can be divided into two subsets based on the presence or absence of a clonal B cell population, and that overt lymphoma can arise from the former subset and contain the same B cell clone identified in the pre-existent CLH lesion.


Housing conditions and ill health.
Lack of empirical evidence that living in damp houses has detrimental effects on health may partly be due to inadequate research. A preliminary study was therefore carried out of a random sample of council owned residences in a deprived area of Edinburgh, a respondent from consenting households being interviewed to obtain a profile of the physical and mental health of all adults and children. In addition, information was gathered about other factors that might be important, particularly smoking and selective bias in the allocation of tenants to houses. Independent measures of dampness were made by environmental health officers. No conclusive effects of damp on the health of adults were identified. Nevertheless, children living in damp houses, especially where fungal mould was present, had higher rates of respiratory symptoms, which were unrelated to smoking in the household, and higher rates of symptoms of infection and stress. Housing should remain an important public health issue, and the effects of damp warrant further investigation.


The use of energy drinks in sport: perceived ergogenicity and side effects in male and female athletes.
The use of caffeine containing energy drinks has dramatically increased in the last few years, especially in the sport context because of its reported ergogenic effect. The ingestion of low to moderate doses of caffeinated energy drinks has been associated with adverse side effects such as insomnia or increased nervousness. The aim of the present study was to assess psycho-physiological changes and the prevalence of side effects resulting from the ingestion of 3 mg caffeine/kg body mass in the form of an energy drink. In a double-blind and placebo controlled experimental design, ninety experienced and low-caffeine-consuming athletes (fifty-three male and thirty-seven female) in two different sessions were provided with an energy drink that contained 3 mg/kg of caffeine or the same decaffeinated energy drink (placebo; 0 mg/kg). At 60 min after the ingestion of the energy drink, participants completed a training session. The effects of ingestion of these beverages on psycho-physiological variables during exercise and the rate of adverse side effects were measured using questionnaires. The caffeinated energy drink increased self-perceived muscle power during exercise compared with the placebo beverage (6·41 (sd 1·7) v. 5·66 (sd 1·51); P= 0·001). Moreover, the energy drink produced a higher prevalence of side effects such as insomnia (31·2 v. 10·4 %; P< 0·001), nervousness (13·2 v. 0 %; P= 0·002) and activeness (16·9 v. 3·9 %; P= 0·007) than the placebo energy drink. There were no sex differences in the incidence of side effects (P>0·05). The ingestion of an energy drink with 3 mg/kg of caffeine increased the prevalence of side effects. The presence of these side effects was similar between male and female participants.


Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition.
Revealing the mechanisms for neuronal somatic diversification remains a central challenge for understanding individual differences in brain organization and function. Here we show that an engineered human LINE-1 (for long interspersed nuclear element-1; also known as L1) element can retrotranspose in neuronal precursors derived from rat hippocampus neural stem cells. The resulting retrotransposition events can alter the expression of neuronal genes, which, in turn, can influence neuronal cell fate in vitro. We further show that retrotransposition of a human L1 in transgenic mice results in neuronal somatic mosaicism. The molecular mechanism of action is probably mediated through Sox2, because a decrease in Sox2 expression during the early stages of neuronal differentiation is correlated with increases in both L1 transcription and retrotransposition. Our data therefore indicate that neuronal genomes might not be static, but some might be mosaic because of de novo L1 retrotransposition events.


Covid-19 in South America: clinical and epidemiological characteristics among 381 patients during the early phase of the pandemic in Santiago, Chile.
Understanding the characteristics of the Covid-19 pandemic in different geographical regions, ethnic and socioeconomic settings are of emerging importance. This study presents the demographic and clinical features of SARS-CoV-2 infected patients in a large private healthcare center in Santiago, Chile, during the first month of the pandemic. We analyzed the demographics, laboratory and clinical characteristics including severity and outcome of all patients diagnosed with Covid-19 during the first month of the pandemic. SARS-2-CoV infection was confirmed by RT-PCR in nosopharyngeal samples. The primary outcome was a composite of ICU admission or all-cause, in-hospital mortality. Clinical and laboratory parameters of hospitalized patients were analyzed regarding their association with the primary outcome. From March 3 to April 4, 2020, 3679 individuals were tested for SARS-CoV-2 in our hospital. Of those, 381 had Covid-19 and were included into this analysis. Most patients (99.2%) were Chileans, 12% returning from recent travel. The median age was 39 years (IQR 31-49) and 52% were female. A total of 88 patients (23.1%) were hospitalized; 18 (3.7%) required ICU and/or died. The overall mortality was 0.7%. Increased body mass index (BMI) and elevated C-reactive protein (CRP) were independently associated with ICU care or death. During the first weeks of the pandemic in Chile, most Covid-19 patients were young, with low rates of hospitalization, ICU requirement, and fatality. BMI and CRP on admission were predictors for severity. Our data provide important information on the clinical course and outcome of Covid-19 in a Latin American setting.


Successfully living with chronic arthritis. The role of the allied health professionals.
The treatment and care of patients with rheumatoid arthritis (RA) is complex and various health professionals with different areas of expertise may be involved. The objective of this article is to review the treatments and their efficacy as provided by health care professionals in RA care. The requirements for further research in this area are formulated. To achieve better effects of treatment it is necessary to improve the coordination of services as provided by the different specialists. The important roles of the patients themselves in the care and management of the disease are emphasized, as well as the roles of the informal caregivers such as a spouse or other family members and friends and the role of patient societies. The possible role of the International Classification of Functioning, Disability and Health (ICF) to improve the communication and facilitate the coordination among health professionals and between patients and health professionals is mentioned. The topics presented in this article may encourage further discussion and research, particularly concerning the effects of the treatments as provided by allied health professionals. Health professionals play an important role in the life of patients with rheumatic disorders, in all the domains of the ICF: body functions and structure, activities (action by an individual) and participation (involvement in a life situation). Health professionals in rheumatology can make the difference in the lives of RA patients and their families.


Upregulation of eIF4E, but not other translation initiation factors, in dendritic spines during memory formation.
Local translation can provide a rapid, spatially targeted supply of new proteins in distal dendrites to support synaptic changes that underlie learning. Learning and memory are especially sensitive to manipulations of translational control mechanisms, particularly those that target the initiation step, and translation initiation at synapses could be a means of maintaining synapse specificity during plasticity. Initiation predominantly occurs via recruitment of ribosomes to the 5' mRNA cap by complexes of eukaryotic initiation factors (eIFs), and the interaction between eIF4E and eIF4G1 is a particularly important target of translational control pathways. Pharmacological inhibition of eIF4E-eIF4G1 binding impairs formation of memory for aversive Pavlovian conditioning as well as the accompanying increase in polyribosomes in the heads of dendritic spines in the lateral amygdala (LA). This is consistent with a role for initiation at synapses in memory formation, but whether eIFs are even present near synapses is unknown. To determine whether dendritic spines contain eIFs and whether eIF distribution is affected by learning, we combined immunolabeling with serial section transmission electron microscopy (ssTEM) volume reconstructions of LA dendrites after Pavlovian conditioning. Labeling for eIF4E, eIF4G1, and eIF2α-another key target of regulation-occurred in roughly half of dendritic spines, but learning effects were only found for eIF4E, which was upregulated in the heads of dendritic spines. Our results support the possibility of regulated translation initiation as a means of synapse-specific protein targeting during learning and are consistent with the model of eIF4E availability as a central point of control.


Fatal transorbital penetrating intracranial injury caused by a bicycle hand brake.
A transorbital penetrating intracranial injury is a rare and severe traumatic brain injury. Patients with this type of injury may present dramatically, but often the injury is subtle and therefore easily overlooked and not recognized in the first place. We present the case of a 45-year-old female admitted to the emergency department after she fell with her bike and the bicycle brake handle penetrated her left eye. A computerized tomography of the cerebrum showed a fracture of the superior orbital roof with multiple bone fragments extending into the brain near the circle of Willis. A pneumocephalus and traumatic frontobasal, intraventricular and subdural hemorrhage was seen. The patient deteriorated suddenly and was transferred to a neurosurgical center where she underwent an emergency craniotomy with evacuation of the intracerebral hematoma and an intraventricular drain was placed. After surgery, the patient's condition deteriorated, and total compression of the brain stem occurred, upon which the patient was declared brain dead. Our case report shows that the Glasgow Coma Scale score at admission is not always a good predictor of the severity of the injury. Even when there is minimal suspicion of a penetrating intracranial injury, a computerized tomography should be performed immediately, independent of the patient's Glasgow Coma Scale score. A direct transfer to a specialized neurosurgical center is recommended because this injury often results in death due to fatal complications such as intracerebral hemorrhage, pneumocephalus and brain stem injury.


Changing material properties of the tree shrew sclera during minus lens compensation and recovery.
To estimate two collagen-specific material properties (crimp angle and elastic modulus of collagen fibrils) of the remodeling tree shrew sclera during monocular -5 diopter (D) lens wear and recovery. Tensile tests were performed on scleral strips obtained from juvenile tree shrews exposed to three different visual conditions: normal, monocular -5 D lens wear to induce myopia, and recovery. Collagen fibrils are crimped in the unloaded sclera and uncrimp as the tissue stiffens under load. Inverse numerical analyses were performed to estimate the (unloaded) crimp angle and elastic modulus of collagen fibrils using a microstructure-based constitutive model. Compared with the control eye, the crimp angle was significantly higher in the treated eye after 2 days and remained significantly higher until 21 days of lens wear (P < 0.05). The difference between the crimp angle of the treated and control eye rapidly vanished during recovery in concert with the changes in axial elongation rate. A rapid and extensive increase in the elastic modulus was seen in both eyes after starting and stopping the lens wear. The estimated change in the crimp of scleral collagen fibrils is temporally associated with the change in axial elongation rate during myopia development and recovery. This finding suggests that axial elongation may be controlled by a remodeling mechanism that modulates the collagen fibril crimp. The observed binocular changes in scleral stiffness are not temporally associated with the axial elongation rate, indicating that scleral stiffening may not be causally related to myopia.


UV light tanning as a type of substance-related disorder.
To better understand the complex motivations involved with UV light (UVL) tanning behavior. Two written instruments, the CAGE (Cut down, Annoyed, Guilty, Eye-opener) Questionnaire, used to screen for alcohol abuse or dependence, and the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria for substance-related disorders, were modified to evaluate subjects for a substance-related disorder involving UVL tanning. Galveston Island beach. Subjects A total of 145 beach-goers. Positive findings from the 2 evaluation instruments. Of the 145 subjects, 38 (26%) met the modified CAGE criteria, and 77 (53%) met the modified DSM-IV-TR diagnostic criteria for a substance-related disorder with regard to UVL and related sun tanning. The results from both instruments were significantly associated (P = .03). Individuals who chronically and repetitively expose themselves to UVL to tan may have a novel type of UVL substance-related disorder.


Reduction of sympathetic activity via adrenal-targeted GRK2 gene deletion attenuates heart failure progression and improves cardiac function after myocardial infarction.
Chronic heart failure (HF) is characterized by sympathetic overactivity and enhanced circulating catecholamines (CAs), which significantly increase HF morbidity and mortality. We recently reported that adrenal G protein-coupled receptor kinase 2 (GRK2) is up-regulated in chronic HF, leading to enhanced CA release via desensitization/down-regulation of the chromaffin cell alpha(2)-adrenergic receptors that normally inhibit CA secretion. We also showed that adrenal GRK2 inhibition decreases circulating CAs and improves cardiac inotropic reserve and function. Herein, we hypothesized that adrenal-targeted GRK2 gene deletion before the onset of HF might be beneficial by reducing sympathetic activation. To specifically delete GRK2 in the chromaffin cells of the adrenal gland, we crossed PNMTCre mice, expressing Cre recombinase under the chromaffin cell-specific phenylethanolamine N-methyltransferase (PNMT) gene promoter, with floxedGRK2 mice. After confirming a significant ( approximately 50%) reduction of adrenal GRK2 mRNA and protein levels, the PNMT-driven GRK2 knock-out (KO) offspring underwent myocardial infarction (MI) to induce HF. At 4 weeks post-MI, plasma levels of both norepinephrine and epinephrine were reduced in PNMT-driven GRK2 KO, compared with control mice, suggesting markedly reduced post-MI sympathetic activation. This translated in PNMT-driven GRK2 KO mice into improved cardiac function and dimensions as well as amelioration of abnormal cardiac beta-adrenergic receptor signaling at 4 weeks post-MI. Thus, adrenal-targeted GRK2 gene KO decreases circulating CAs, leading to improved cardiac function and beta-adrenergic reserve in post-MI HF. GRK2 inhibition in the adrenal gland might represent a novel sympatholytic strategy that can aid in blocking HF progression.


Opioid replacement therapy: a wait unmanaged.
There has been a rapid increase in members of the Australian population using opioids in recent years. The flow-on effect has been an increase in demand for treatments, particularly opioid replacement therapy (ORT), but the availability of treatments has not increased. This has frequently resulted in delays before treatment can be commenced. Outcomes could improve if health-care professionals had clearer guidelines on how to prioritize access to ORT. This review investigates the triage of consumers in ORT within Australia. Information on triage in ORT was not available, and an understanding of how consumer needs are managed when they present for ORT triage was not identified. In the absence of research to guide this practice, the body of evidence regarding ORT treatment access is weighted on government policies. Triage, as applied in general health and mental health-care service delivery, was reviewed to consider the components of triage and how these might pertain to triage in ORT. Failure to facilitate the needs of consumers accessing ORT can result in further harm to consumers and increased social and financial costs for society. Research is required to investigate how this issue is currently being managed and to lead the way for needed improvements in service delivery.


Leg-length discrepancy: effect on the amplitude of postural sway.
The purpose of this study was to investigate whether leg-length discrepancy (LLD) influences a person's standing balance as measured by the amplitude of his/her postural sway. Twenty volunteers between the ages of 20 and 32 participated. Eleven individuals with no measurable LLD constituted the control group. The experimental group consisted of nine individuals with at least a 9.5mm LLD. Each subject stood barefoot on a force platform with their feet together. Center-of-pressure data were collected at a rate of 10Hz for 12.8 seconds while the subjects stood with their eyes opened and again with their eyes closed. The amplitude of each person's postural sway in the medial-lateral and anterior-posterior directions was calculated from the center-of-pressure data. The results of the study showed that no significant difference existed between the experimental and control groups. There was, however, a significant difference (p less than .05) between the conditions of eyes opened and closed. These results indicate that individuals with an LLD do not have more postural sway than those without an LLD.


Presymptomatic Fibrous Root Decline in Citrus Trees Caused by Huanglongbing and Potential Interaction with Phytophthora spp.
Huanglongbing (HLB), associated with 'Candidatus Liberibacter asiaticus', was first detected in Florida in late 2005 and is now widely distributed throughout the commercial citrus-growing regions. In recent seasons, concurrent with freeze and drought episodes, symptomatic HLB-infected trees were much more affected by the extremes of temperature and moisture than trees without HLB. Symptoms exhibited by the stressed trees were excessive leaf loss and premature fruit drop even when HLB-infected trees were managed with good nutritional and irrigation practices recommended to support health of HLB-affected trees. This stress intolerance may be due to a loss of fibrous roots. To assess root status of HLB-infected trees on 'Swingle' citrumelo rootstock (Citrus paradisi × Poncirus trifoliata), blocks of 2,307 3-year-old 'Hamlin' orange trees and 2,693 4-year-old 'Valencia' orange trees were surveyed visually and with a real-time polymerase chain reaction (PCR) assay to determine 'Ca. L. asiaticus' infection status. The incidence of 'Ca. L. asiaticus'-infected trees (presymptomatic: 'Ca. L. asiaticus'+, visually negative; and symptomatic: 'Ca. L. asiaticus'+, visually positive) trees was 89% for the Hamlin block and 88% for the Valencia block. 'Ca. L. asiaticus'+ trees had 30 and 37% lower fibrous root mass density for presymptomatic and symptomatic trees, respectively, compared with 'Ca. L. asiaticus'- trees. In a second survey, 10- to 25-year-old Valencia trees on Swingle citrumelo or 'Carrizo' citrange (C. sinensis (L.) × P. trifoliata) rootstock were sampled within 3 to 6 months after identification of visual HLB status as symptomatic ('Ca. L. asiaticus'+, visually positive) or nonsymptomatic ('Ca. L. asiaticus'-, visually negative) in orchards located in the central ridge, south-central, and southwest flatwoods. Pairs of HLB symptomatic and nonsymptomatic trees were evaluated for PCR status, fibrous root mass density, and Phytophthora nicotianae propagules in the rhizosphere soil. 'Ca. L. asiaticus'+ trees had 27 to 40% lower fibrous root mass density and, in one location, higher P. nicotianae per root but Phytophthora populations per cubic centimeter of soil were high on both 'Ca. L. asiaticus'+ and 'Ca. L. asiaticus'- trees. Fibrous root loss from HLB damage interacted with P. nicotianae depending on orchard location and time of year.


Rapid activation of spleen dendritic cell subsets following lymphocytic choriomeningitis virus infection of mice: analysis of the involvement of type 1 IFN.
In this study, we report the dynamic changes in activation and functions that occur in spleen dendritic cell (sDC) subsets following infection of mice with a natural murine pathogen, lymphocytic choriomeningitis virus (LCMV). Within 24 h postinfection (pi), sDCs acquired the ability to stimulate naive LCMV-specific CD8+ T cells ex vivo. Conventional (CD11chigh CD8+ and CD4+) sDC subsets rapidly up-regulated expression of costimulatory molecules and began to produce proinflammatory cytokines. Their tendency to undergo apoptosis ex vivo simultaneously increased, and in vivo the number of conventional DCs in the spleen decreased markedly, dropping approximately 2-fold by day 3 pi. Conversely, the number of plasmacytoid (CD11clowB220+) DCs in the spleen increased, so that they constituted almost 40% of sDCs by day 3 pi. Type 1 IFN production was up-regulated in plasmacytoid DCs by 24 h pi. Analysis of DC activation and maturation in mice unable to respond to type 1 IFNs implicated these cytokines in driving infection-associated phenotypic activation of conventional DCs and their enhanced tendency to undergo apoptosis, but also indicated the existence of type 1 IFN-independent pathways for the functional maturation of DCs during LCMV infection.


Reflex cardiovascular responses evoked by selective activation of skeletal muscle ergoreceptors.
It is well known that the exercise pressor reflex (EPR) is mediated by group III and IV skeletal muscle afferent fibers, which exhibit unique discharge responses to mechanical and chemical stimuli. Based on the difference in discharge patterns of group III and IV muscle afferents, we hypothesized that activation of mechanically sensitive (MS) fibers would evoke a different pattern of cardiovascular responses compared with activation of both MS and chemosensitive (CS) fibers. Experiments were conducted in chloralose-urethane-anesthetized cats (n = 10). Passive muscle stretch was used to activate MS afferents, and electrically evoked contraction of the triceps surae was used to activate both MS and CS muscle afferents. No significant differences were shown in reflex heart rate and mean arterial pressure (MAP) responses between passive muscle stretch and evoked muscle contraction. However, when the reflex responses were matched according to tension-time index (TTI), the peak MAP response (67 +/- 4 vs. 56 +/- 4 mmHg, P < 0.05) was significantly greater at higher TTI (427 +/- 18 vs. 304 +/- 13 kg. s, high vs. low TTI, P < 0.05), despite different modes of afferent fiber activation. When the same mode of afferent fiber activation was compared, the peak MAP response (65 +/- 7 vs. 55 +/- 5 mmHg, P < 0.05) was again predicted by the magnitude of TTI (422 +/- 24 vs. 298 +/- 19 kg. s, high vs. low TTI, P < 0.05). Total sensory input from skeletal muscle ergoreceptors, as predicted by TTI and not the modality of afferent fiber activation (muscle contraction vs. passive stretch), is suggested to be the primary determinant of the magnitude of the EPR-evoked cardiovascular response.


Radionuclide molecular imaging using Affibody molecules.
The current way to increase efficacy of cancer therapy is the use of molecular recognition of aberrantly expressed gene products for selective treatment. However, only a fraction of the patients have tumors with a particular molecular target. Radionuclide imaging of molecular targets might help to stratify patient for cancer treatment. Affibody molecules are scaffold proteins, which can be selected for high affinity recognition of proteinaceous molecular targets. The capacity to re-fold under physiological conditions allows labeling of Affibody molecules in a broad range of pH and temperatures with preserved binding properties. Peptide synthesis or introduction of a unique cysteine enables site-specific labeling of Affibody molecules, resulting in uniform conjugates with well-defined pharmacological characteristics. The small size (7 kDa) of Affibody molecules provides rapid extravasation, rapid tumor penetration, and rapid clearance of unbound tracer from healthy organs and tissues. In combination with sub-nanomolar affinity, this results in high contrast in vivo imaging a few hours after injection. Excellent targeting has been demonstrated in pre-clinical studies with HER2-targeting Affibody molecules labeled with (99m)Tc and (111)In for single photon computed tomography (SPECT), and (18)F, (64)Cu, (124)I and (68)Ga for positron emission tomography (PET). Pilot clinical data confirm the high potential of Affibody molecules.


Banding without resection (endoscopic mucosal ligation) as a novel approach for the ablation of short-segment Barrett's epithelium: results of a pilot study.
During an endoscopic variceal ligation, we banded a varix with an overlying tongue of Barrett's epithelium (BE). One month later, the tongue was no longer visible, suggesting that banding could be used to eradicate BE. To assess the safety and efficacy of banding without resection (BWR) using a variceal banding device for eradicating BE. From April 2004 through September 2005, 30 patients with BE were treated with BWR plus omeprazole 20 mg t.i.d. BWR was repeated monthly until two consecutive endoscopic and histological examinations showed no BE. Thirty Barrett's patients treated with omeprazole 20 mg t.i.d. alone served as a control group. The BWR treatment group comprised 29 patients with short-segment BE (SSBE) and one with long-segment disease, whereas all 30 of the control patients had SSBE. During a median follow-up of 16.9 months (range 10-24 months), complete eradication of BE was achieved in 29 of 30 patients (97%) in the BWR group. In contrast, BE persisted in all 30 control patients during the same period (P < 0.0005). The mean total number of bands applied per patient was 6.1 (range 1-14) and the mean number of sessions for complete eradication was 3.1 (range 1-7). Adverse events included only mild chest pain and dysphagia that resolved within days. BWR appears to be a safe, effective, simple, and widely available technique for eradicating SSBE. This is a pilot study and we do not recommend the ablation of nondysplastic BE at this time. Further studies are needed.


Use of Music for Newborns After Cardiac Surgery: A Pilot Study.
Music can benefit the neurodevelopmental and clinical care of newborns in the neonatal intensive care unit. Newborns in the cardiac intensive care unit experience similar stressors to those in the neonatal intensive care unit, but music therapy has not been widely studied in the cardiac intensive care unit population. To explore the feasibility of implementing nurse-led music therapy in a cohort of newborns recovering from cardiac surgery in the cardiac intensive care unit. Lullabies were prerecorded and played for 20 minutes, 2 times per day. Bedside nurses recorded several metrics at designated times during the 1 hour surrounding the music therapy and were asked about the ease of initiating the therapy and their perception of any benefit to the newborns. Parents were invited to complete a 9-question Likert survey exploring their perception of and satisfaction with the music therapy. Nurse-led music therapy was initiated in 44 of 50 eligible shifts (88%) for the 8 newborns who successfully completed the study. The newborns' physiological status remained stable throughout the music therapy sessions. None of the newborns experienced adverse events related to music therapy. All nurses (100%) reported that the music therapy was easy to administer. Parents "agreed" or "strongly agreed" that they were satisfied with the music therapy provided to their newborns. Nurse-led music therapy was highly feasible for hemodynamically stable newborns recovering from cardiac surgery. Parents and nursing staff responded positively to the music therapy.


Segmenting and tracking fluorescent cells in dynamic 3-D microscopy with coupled active surfaces.
Cell migrations and deformations play essential roles in biological processes, such as parasite invasion, immune response, embryonic development, and cancer. We describe a fully automatic segmentation and tracking method designed to enable quantitative analyses of cellular shape and motion from dynamic three-dimensional microscopy data. The method uses multiple active surfaces with or without edges, coupled by a penalty for overlaps, and a volume conservation constraint that improves outlining of cell/cell boundaries. Its main advantages are robustness to low signal-to-noise ratios and the ability to handle multiple cells that may touch, divide, enter, or leave the observation volume. We give quantitative validation results based on synthetic images and show two examples of applications to real biological data.


Searching the internet for help with pain: adolescent search, coping, and medication behaviour.
To explore a community sample of adolescents for engagement with online pain resources. To assess if the use of the Internet to search for health information correlated with measures of coping, risk taking, catastrophizing about pain, and engaging in the self-management of pain. A cross-sectional online study of community-based adolescents (n = 105) recruited via schools to examine their use of the Internet to seek pain-related information. Adolescents completed questionnaires of pain coping, catastrophic thinking, risk-taking behaviour, and medication use. Descriptive analyses were undertaken on event rates of pertinent behaviours, principally on information seeking and pain management behaviour. Correlational analyses were undertaken between coping and information seeking, and medication use. Few participants engaged in online pain information seeking. Those who did were more likely to be female and scored higher on medication use, catastrophizing, risk taking, and the total score on the Pain Coping Questionnaire. Although adolescents are high users of the Internet, paradoxically they do not appear to use the Internet for information about pain and pain management. Further research should assess inhibitory and disinhibitory factors associated with information seeking about pain and chronic illness on the Internet. What is already known on this subject? Internet use in adolescents is common, mobile, and displays a level of technical awareness unparalleled by adults. The internet is postulated in previous research to present a platform for the delivery of health care, particularly information to aid health decision-making for young people. What does this study add? This study explores how adolescents use the internet to look for health information, particularly on pain and where this falls in a general profile of coping with illness. Interestingly and counterintuitively, adolescents did not use the internet to look for health or pain information. We hypothesize that there may be something about information on pain management that does not readily transfer to the digital world in a way that is useful to adolescent users.


The origin of dorsoventral polarity in Drosophila.
In Drosophila dorsoventral (DV) polarity arises during oogenesis when the oocyte nucleus moves from a central posterior to an asymmetrical anterior position. Nuclear movement is a symmetry-breaking step and establishes orthogonality between the anteroposterior and the DV axes. The asymmetrically anchored nucleus defines a cortical region within the oocyte which accumulates high levels of gurken messenger RNA (mRNA) and protein. Gurken is an ovarian-specific member of the transforming growth factor-alpha (TGF-alpha) family of secreted ligands. Secreted Gurken forms a concentration gradient that results in a dorsal-to-ventral gradient of EGF receptor activation in the follicle cells surrounding the oocyte. This leads to concentration-dependent activation or repression of target genes of the EGF pathway in the follicular epithelium. One outcome of this process is the restriction of pipe expression to a ventral domain that comprises 40% of the egg circumference. Pipe presumably modifies extracellular matrix components that are secreted by the follicle cells and are present at the ventral side of embryo after egg deposition. Here, they activate a proteolytic cascade that generates a gradient of the diffusible ligand, Spätzle. Spätzle activates the Toll receptor at the surface of the embryo that stimulates the nuclear uptake of the transcription factor Dorsal. This leads to a nuclear concentration gradient of Dorsal that specifies the cell types along the DV axis of the embryo.


Tomographic imaging of temperature and chemical species based on hyperspectral absorption spectroscopy.
A novel technique has been developed to obtain simultaneous tomographic images of temperature and species concentration based on hyperspectral absorption spectroscopy. The hyperspectral information enables several key advantages when compared to traditional tomography techniques based on limited spectral information. These advantages include a significant reduction in the number of required projection measurements, and an enhanced insensitivity to measurements/inversion uncertainties. These advantages greatly facilitate the practical implementation and application of the tomography technique. This paper reports the development of the technique, and the experimental demonstration of a prototype sensor in a near-adiabatic, atmospheric-pressure laboratory Hencken burner. The spatial and temporal resolution enabled by this new sensing technique is expected to resolve several key issues in practical combustion devices.


Cophenetic correlation analysis as a strategy to select phylogenetically informative proteins: an example from the fungal kingdom.
The construction of robust and well resolved phylogenetic trees is important for our understanding of many, if not all biological processes, including speciation and origin of higher taxa, genome evolution, metabolic diversification, multicellularity, origin of life styles, pathogenicity and so on. Many older phylogenies were not well supported due to insufficient phylogenetic signal present in the single or few genes used in phylogenetic reconstructions. Importantly, single gene phylogenies were not always found to be congruent. The phylogenetic signal may, therefore, be increased by enlarging the number of genes included in phylogenetic studies. Unfortunately, concatenation of many genes does not take into consideration the evolutionary history of each individual gene. Here, we describe an approach to select informative phylogenetic proteins to be used in the Tree of Life (TOL) and barcoding projects by comparing the cophenetic correlation coefficients (CCC) among individual protein distance matrices of proteins, using the fungi as an example. The method demonstrated that the quality and number of concatenated proteins is important for a reliable estimation of TOL. Approximately 40-45 concatenated proteins seem needed to resolve fungal TOL. In total 4852 orthologous proteins (KOGs) were assigned among 33 fungal genomes from the Asco- and Basidiomycota and 70 of these represented single copy proteins. The individual protein distance matrices based on 531 concatenated proteins that has been used for phylogeny reconstruction before 14 were compared one with another in order to select those with the highest CCC, which then was used as a reference. This reference distance matrix was compared with those of the 70 single copy proteins selected and their CCC values were calculated. Sixty four KOGs showed a CCC above 0.50 and these were further considered for their phylogenetic potential. Proteins belonging to the cellular processes and signaling KOG category seem more informative than those belonging to the other three categories: information storage and processing; metabolism; and the poorly characterized category. After concatenation of 40 proteins the topology of the phylogenetic tree remained stable, but after concatenation of 60 or more proteins the bootstrap support values of some branches decreased, most likely due to the inclusion of proteins with lowers CCC values. The selection of protein sequences to be used in various TOL projects remains a critical and important process. The method described in this paper will contribute to a more objective selection of phylogenetically informative protein sequences. This study provides candidate protein sequences to be considered as phylogenetic markers in different branches of fungal TOL. The selection procedure described here will be useful to select informative protein sequences to resolve branches of TOL that contain few or no species with completely sequenced genomes. The robust phylogenetic trees resulting from this method may contribute to our understanding of organismal diversification processes. The method proposed can be extended easily to other branches of TOL.


100 W-level Tm-doped fiber laser pumped by 1173 nm Raman fiber lasers.
We present a high power and high efficiency Tm-doped fiber laser (TDFL) pumped by two high power Raman fiber lasers (RFLs) at 1173 nm. The output power of the TDFL reached 96 W with slope efficiency of 0.42. The central wavelength located at 1943.3 nm with a 3 dB bandwidth of 0.1 nm. Higher output power can be achieved if more RFLs are employed to pump the TDFL. This is to our knowledge the first demonstration with 100 W-level output power achieved in TDFLs around their ∼1200 nm absorption band pumped by RFLs, which indicates a promising and powerful pump scheme to achieve higher power output in TDFLs.


Statistical methods for cost-effectiveness analyses that use data from cluster randomized trials: a systematic review and checklist for critical appraisal.
The best data for cost-effectiveness analyses (CEAs) of group-level interventions often come from cluster randomized trials (CRTs), where randomization is by cluster (e.g., the hospital attended), not by individual. for these CEAs need to recognize both the correlation between costs and outcomes and that these data may be dependent on the cluster. General checklists and methodological guidance for critically appraising CEA ignore these issues. This article develops a new checklist and applies it in a systematic review of CEAs that use CRTs. The authors developed a checklist for CEAs that use CRTs, informed by a conceptual review of statistical methods. This checklist included criteria such as whether the analysis allowed for both clustering and the correlation between individuals' costs and outcomes. The authors undertook a systematic literature review of full economic evaluations that used CRTs. The quality of studies was assessed with the new checklist and by the "Drummond checklist." The authors identified 62 papers that met the inclusion criteria. On average, studies satisfied 9 of the 10 criteria for the checklist but only 20% of criteria for the new checklist. More than 40% of studies adopted statistical methods that completely ignored clustering, and 75% disregarded any correlation between costs and outcomes. Only 4 studies employed appropriate statistical methods that allowed for both clustering and correlation. Most economic evaluations that use data from CRTs ignored clustering or correlation. Statistical methods that address these issues are available, and their use should be encouraged. The new checklist can supplement generic CEA guidelines and highlight where research practice can be improved.


Morphine and galectin-1 modulate HIV-1 infection of human monocyte-derived macrophages.
Morphine is a widely abused, addictive drug that modulates immune function. Macrophages are a primary reservoir of HIV-1; therefore, they play a role in the development of this disease, as well as impact the overall course of disease progression. Galectin-1 is a member of a family of β-galactoside-binding lectins that are soluble adhesion molecules and that mediate direct cell-pathogen interactions during HIV-1 viral adhesion. Because the drug abuse epidemic and the HIV-1 epidemic are closely interrelated, we propose that increased expression of galectin-1 induced by morphine may modulate HIV-1 infection of human monocyte-derived macrophages (MDMs). In this article, we show that galectin-1 gene and protein expression are potentiated by incubation with morphine. Confirming previous studies, morphine alone or galectin-1 alone enhance HIV-1 infection of MDMs. Concomitant incubation with exogenous galectin-1 and morphine potentiated HIV-1 infection of MDMs. We used a nanotechnology approach that uses gold nanorod-galectin-1 small interfering RNA complexes (nanoplexes) to inhibit gene expression for galectin-1. We found that nanoplexes silenced gene expression for galectin-1, and they reversed the effects of morphine on galectin-1 expression. Furthermore, the effects of morphine on HIV-1 infection were reduced in the presence of the nanoplex.


Variation in quality of diabetes care at the levels of patient, physician, and clinic.
We studied variance in glycated hemoglobin (HbA1c) values among adults with diabetes to identify variation in quality of diabetes care at the levels of patient, physician, and clinic, and to identify which levels contribute the most to variation and which variables at each level are related to quality of diabetes care. Study subjects were 120 primary care physicians and their 2589 eligible adult patients with diabetes seen at 18 clinics. The dependent variable was HbA1c values recorded in clinical databases. Multivariate hierarchical models were used to partition variation in HbA1c values across the levels of patient, physician, or clinic and to identify significant predictors of HbA1c at each level. More than 95% of variance in HbA1c values was attributable to the patient level. Much less variance was seen at the physician and clinic level. Inclusion of patient and physician covariates did not substantially change this pattern of results. Intensification of pharmacotherapy (t = -7.40, P < .01) and patient age (t = 2.10, P < .05) were related to favorable change in HbA1c. Physician age, physician specialty, number of diabetes patients per physician, patient comorbidity, and clinic assignment did not predict change in HbA1c value. The overall model with covariates explained 11.8% of change in HbA1c value over time. These data suggest that most variance in HbA1c values is attributable to patient factors, although physicians play a major role in some patient factors (e.g., intensification of medication). These findings may lead to more effective care-improvement strategies and accountability measures.


Biodegradation of marine oil spills in the Arctic with a Greenland perspective.
New economic developments in the Arctic, such as shipping and oil exploitation, bring along unprecedented risks of marine oil spills. Microorganisms have played a central role in degrading and reducing the impact of the spilled oil during past oil disasters. However, in the Arctic, and in particular in its pristine areas, the self-cleaning capacity and biodegradation potential of the natural microbial communities have yet to be uncovered. This review compiles and investigates the current knowledge with respect to environmental parameters and biochemical constraints that control oil biodegradation in the Arctic. Hereby, seawaters off Greenland are considered as a case study. Key factors for biodegradation include the bioavailability of hydrocarbons, the presence of hydrocarbon-degrading bacteria and the availability of nutrients. We show how these key factors may be influenced by the physical oceanographic conditions in seawaters off Greenland and other environmental parameters including low temperature, sea ice, sunlight regime, suspended sediment plumes and phytoplankton blooms that characterize the Arctic. Based on the acquired insights, a first qualitative assessment of the biodegradation potential in seawaters off Greenland is presented. In addition to the most apparent Arctic characteristics, such as low temperature and sea ice, the impact of typical Arctic features such as the oligotrophic environment, poor microbial adaptation to hydrocarbon degradation, mixing of stratified water masses, and massive phytoplankton blooms and suspended sediment plumes merit to be topics of future investigation.


Adult T-cell leukaemia/lymphoma.
Adult T-cell leukaemia/lymphoma (ATLL) is a mature T-cell neoplasm of post-thymic lymphocytes aetiologically linked to the human T-cell lymphotropic virus, HTLV-I, and with a distinct geographical distribution. The disease manifests with leukaemia in greater than two thirds of patients, while the remaining patients have a lymphomatous form. According to the disease manifestations, various forms which differ in clinical course and prognosis have been recognised: acute, chronic, smouldering and lymphoma. Organomegaly, skin involvement, circulating atypical lymphocytes ("flower" cells) with a CD4+ CD25+ phenotype and hypercalcaemia are the most common disease features. The diagnosis should be based on a constellation of clinical features and laboratory investigations. The latter comprise: lymphocyte morphology, immunophenotype, histology of the tissues affected in the pure lymphoma forms and serology or DNA analysis for HTLV-I. The differential diagnosis of ATLL includes other mature T-cell neoplasms such as T-cell prolymphocytic leukaemia (T-PLL), Sézary syndrome (SS), peripheral T-cell lymphomas and occasionally healthy carriers of the virus or Hodgkin disease. The clinical course is aggressive with a median survival of less than 12 months in the acute and lymphoma forms. Despite major advances in understanding the pathogenesis of the disease, management of these patients remains a challenge for clinicians as they do not respond or achieve only transient responses to therapies used in high-grade lymphomas. The use of antiretroviral agents such as zidovudine in combination with interferon-alpha, with or without concomitant chemotherapy, has shown activity in this disease with improvement in survival and response rate. Consolidation with high dose therapy and autologous or allogeneic stem-cell transplantation should be considered in young patients.


Abnormal myofiber morphology and limb dysfunction in claudication.
Peripheral artery disease (PAD), which affects an estimated 27 million people in Europe and North America, is caused by atherosclerotic plaques that limit blood flow to the legs. Chronic, repeated ischemia in the lower leg muscles of PAD patients is associated with loss of normal myofiber morphology and myofiber degradation. In this study, we tested the hypothesis that myofiber morphometrics of PAD calf muscle are significantly different from normal calf muscle and correlate with reduced calf muscle strength and walking performance. Gastrocnemius biopsies were collected from 154 PAD patients (Fontaine stage II) and 85 control subjects. Morphometric parameters of gastrocnemius fibers were determined and evaluated for associations with walking distances and calf muscle strength. Compared with control myofibers, PAD myofiber cross-sectional area, major and minor axes, equivalent diameter, perimeter, solidity, and density were significantly decreased (P < 0.005), whereas roundness was significantly increased (P < 0.005). Myofiber morphometric parameters correlated with walking distances and calf muscle strength. Multiple regression analyses demonstrated myofiber cross-sectional area, roundness, and solidity as the best predictors of calf muscle strength and 6-min walking distance, whereas cross-sectional area was the main predictor of maximum walking distance. Myofiber morphometrics of PAD gastrocnemius differ significantly from those of control muscle and predict calf muscle strength and walking distances of the PAD patients. Morphometric parameters of gastrocnemius myofibers may serve as objective criteria for diagnosis, staging, and treatment of PAD.


African American women share 'real talk' stories about fatigue related to breast cancer treatment.
Fatigue is the most common side effect experienced by women undergoing treatment for breast cancer. The fatigue experience of African American (AA) women who undergo breast cancer treatment has been understudied. The purpose of this qualitative exploratory study is to share stories of 10 AA women who experienced fatigue related to breast cancer treatment. AA women provided real talk descriptors of fatigue. Women expressed how physicians were supportive of their exercising to manage their fatigue. However, many women describe the medications prescribed for fatigue as not very helpful or even making them feel worse. Women shared use of complementary treatment approaches and that their physicians approved of such complementary treatment use. All the participants described how they relied on prayer for their spiritual strength to deal with the overwhelming effects of fatigue on their daily lives. An understanding by health care practitioners of the fatigue and coping experiences related to breast cancer among AA women can provide better ways for health care practitioners to treat and help their AA patients address fatigue symptoms.


The role of B cells and humoral immunity in Mycobacterium tuberculosis infection.
Tuberculosis (TB) remains a serious threat to public health, causing 2 million deaths annually world-wide. The control of TB has been hindered by the requirement of long duration of treatment involving multiple chemotherapeutic agents, the increased susceptibility to Mycobacterium tuberculosis infection in the HIV-infected population, and the development of multi-drug resistant and extensively resistant strains of tubercle bacilli. An efficacious and cost-efficient way to control TB is the development of effective anti-TB vaccines. This measure requires thorough understanding of the immune response to M. tuberculosis. While the role of cell-mediated immunity in the development of protective immune response to the tubercle bacillus has been well established, the role of B cells in this process is not clearly understood. Emerging evidence suggests that B cells and humoral immunity can modulate the immune response to various intracellular pathogens, including M. tuberculosis. These lymphocytes form conspicuous aggregates in the lungs of tuberculous humans, non-human primates, and mice, which display features of germinal center B cells. In murine TB, it has been shown that B cells can regulate the level of granulomatous reaction, cytokine production, and the T cell response. This chapter discusses the potential mechanisms by which specific functions of B cells and humoral immunity can shape the immune response to intracellular pathogens in general, and to M. tuberculosis in particular. Knowledge of the B cell-mediated immune response to M. tuberculosis may lead to the design of novel strategies, including the development of effective vaccines, to better control TB.


Intrinsic and extrinsic mechanisms of oocyte loss.
A great deal of evolutionary conservation has been found in the control of oocyte development, from invertebrates to women. However, little is known of mechanisms that control oocyte loss over time. Oocyte loss is often assumed to be a result of oocyte-intrinsic deficiencies or damage. In fruit flies, starvation results in halted oocyte production by germline stem cells and induces oocyte loss midway through development. When we fed wild-type flies the bacterial compound Rapamycin (RAP) to mimic starvation, production of new oocytes continued, but mid-stage loss sterilized the animals. Surprisingly, follicle cell invasion and phagocytosis of the oocyte preceded any signs of germ cell death. RAP-induced egg chamber loss was prevented when RAP receptor FKBP12 was knocked down specifically in follicle cells. Oogenesis continued past the mid-stages, and these mutants continued to lay embryos that could develop into normal adults. Hence, intact healthy oocytes can be destroyed by somatic cells responding to extrinsic stimuli. We termed this process inducible somatic oocyte destruction. RAP treatment of mouse follicles in vitro resulted in phagocytic uptake of the oocyte by granulosa cells as seen in flies. We hypothesize that extrinsic modes of oocyte loss occur in mammals.


Differential regulation by TGF-beta 1 and insulin of insulin-like growth factor binding protein-2 in IEC-6 cells.
The purposes of this study were to determine the regulation of insulin-like growth factor binding protein-2 (IGFBP-2) in IEC-6 cells by transforming growth factor-beta 1 (TGF-beta 1) and insulin and to determine whether IGFBP-2 mediated the growth-inhibitory action on the cells. Utilizing Western ligand blot analysis, we found that TGF-beta 1 at concentrations of 0.5, 1.0, and 2 ng/ml significantly increased levels of 32-kDa IGFBP in the conditioned medium (CM) of IEC-6 cells in a dose-dependent fashion and that low doses of insulin (1.0 and 5.0 microgram/ml) also increased IGFBP levels in the CM of IEC-6 cells, but a high dose of insulin (10 micrograms/ml) depressed IGFBP release in the CM. Immunoblotting has shown that the IGFBP of 32 kDa was IGFBP-2 and further confirmed the above results. IGFBP-2 mRNA levels were stimulated by TGF-beta 1 (2.0 ng/ml) and suppressed by insulin (5.0 micrograms/ml). In addition, des (1-3) IGF-I (50 ng/ml) and insulin stimulated the proliferation of IEC-6 cells. Anti-IGFBP-2 antibodies partially blocked the inhibitory role in IEC-6 cell growth evoked by des (1-3) IGF-I. These findings suggest that the upregulation of IGFBP-2 by TGF-beta 1 occurs, at least in part, at the level of mRNA, whereas the regulation by insulin appears to be at a posttranslational level, and that the TGF-beta 1-stimulated production of IGFBP may contribute to the growth-inhibitory action in intestinal epithelial cells.


Combined use of platelet rich plasma and vitamin C positively affects differentiation in vitro to mesodermal lineage of adult adipose equine mesenchymal stem cells.
Repair of injured soft and hard tissues in horses can benefit greatly from the use of regenerative therapies with mesenchymal stem cells (MSC). Vitamin-C and platelet-rich-plasma had been used for in vitro differentiation of MSC. This study was aimed to evaluate the effect of vitamin-C, platelet-rich-plasma and their combination on the in vitro differentiation of adipose horse MSC. We isolated MSC from horse fat and differentiated them in vitro into osteogenic and chondrogenic lineages, as demonstrated by specific staining and RT-qPCR of selected genes. Combining vitamin-C and plasma-rich-platelet positively affected the ability of MSC to differentiate in vitro into mesodermal lineages during 14 days of culture; this effect was not as marked when differentiation was attempted for 21 days. This provides valuable information on the effect of combined use of these molecules in regenerative therapies and their potential application along stem cells for lesions of musculoskeletal tissue in sport horses.


Association between serum homocysteine level and cognitive function in middle-aged type 2 diabetes mellitus patients.
Type-2 diabetes mellitus (T2DM) is strongly associated with various complications, including cognitive impairment. Diabetic complication is related with structural and functional changes of brain. Studies investigated that homocysteine as an independent risk factor of several organ complications. This marker might have a role in pathogenesis of cognitive impairment in T2DM patients. We aimed to know the association between serum homocysteine level and cognitive impairment in middle-aged T2DM populations. The study was a cross-sectional study involving 97 T2DM patients aged <60 years old. Cognitive assessment was based on validated Indonesian version of Montreal Cognitive Assessment (MoCA-INA) test. Besides, serum homocysteine level (Hcy) was measured based on standard laboratory assay. Filling out the questionnaire of MoCA-INA was conducted when patients came to take the blood sample. This study used independent t-test, chi-square and multivariate logistic regression model to analyze the data. There were 47 subjects (48.5%) with mild cognitive impairment (MCI). Delayed recall was the most impaired domain (94.8%). There was no significant mean difference of serum Hcy level in MCI and non-MCI group (11.99±3.27 μmol/L vs 12.36±4.07 μmol/L respectively, p = 0.62). Final model of logistic regression showed no association between serum Hcy and cognitive function after adjusting confounding variables (OR: 1.778; 95%CI: 0.69-4.54). Further investigation involving slight elderly T2DM patients with larger sample size should be conducted to confirm this finding.


American College of Sports Medicine position stand. Exercise and fluid replacement.
This Position Stand provides guidance on fluid replacement to sustain appropriate hydration of individuals performing physical activity. The goal of prehydrating is to start the activity euhydrated and with normal plasma electrolyte levels. Prehydrating with beverages, in addition to normal meals and fluid intake, should be initiated when needed at least several hours before the activity to enable fluid absorption and allow urine output to return to normal levels. The goal of drinking during exercise is to prevent excessive (>2% body weight loss from water deficit) dehydration and excessive changes in electrolyte balance to avert compromised performance. Because there is considerable variability in sweating rates and sweat electrolyte content between individuals, customized fluid replacement programs are recommended. Individual sweat rates can be estimated by measuring body weight before and after exercise. During exercise, consuming beverages containing electrolytes and carbohydrates can provide benefits over water alone under certain circumstances. After exercise, the goal is to replace any fluid electrolyte deficit. The speed with which rehydration is needed and the magnitude of fluid electrolyte deficits will determine if an aggressive replacement program is merited.


Toward an Evidence-Based Definition and Classification of Carbohydrate Food Quality: An Expert Panel Report.
Carbohydrate-containing crops provide the bulk of dietary energy worldwide. In addition to their various carbohydrate forms (sugars, starches, fibers) and ratios, these foods may also contain varying amounts and combinations of proteins, fats, vitamins, minerals, phytochemicals, prebiotics, and anti-nutritional factors that may impact diet quality and health. Currently, there is no standardized or unified way to assess the quality of carbohydrate foods for the overall purpose of improving diet quality and health outcomes, creating an urgent need for the development of metrics and tools to better define and classify high-quality carbohydrate foods. The present report is based on a series of expert panel meetings and a scoping review of the literature focused on carbohydrate quality indicators and metrics produced over the last 10 years. The report outlines various approaches to assessing food quality, and proposes next steps and principles for developing improved metrics for assessing carbohydrate food quality. The expert panel concluded that a composite metric based on nutrient profiling methods featuring inputs such as carbohydrate-fiber-sugar ratios, micronutrients, and/or food group classification could provide useful and informative measures for guiding researchers, policymakers, industry, and consumers towards a better understanding of carbohydrate food quality and overall healthier diets. The identification of higher quality carbohydrate foods could improve evidence-based public health policies and programming-such as the 2025-2030 Dietary Guidelines for Americans.


Subclinical carbon monoxide limits apoptosis in the developing brain after isoflurane exposure.
Volatile anesthetics cause widespread apoptosis in the developing brain. Carbon monoxide (CO) has antiapoptotic properties, and exhaled endogenous CO is commonly rebreathed during low-flow anesthesia in infants and children, resulting in subclinical CO exposure. Thus, we aimed to determine whether CO could limit isoflurane-induced apoptosis in the developing brain. Seven-day-old male CD-1 mouse pups underwent 1-hour exposure to 0 (air), 5, or 100 ppm CO in air with or without isoflurane (2%). We assessed carboxyhemoglobin levels, cytochrome c peroxidase activity, and cytochrome c release from forebrain mitochondria after exposure and quantified the number of activated caspase-3 positive cells and TUNEL positive nuclei in neocortex, hippocampus, and hypothalamus/thalamus. Carboxyhemoglobin levels approximated those expected in humans after a similar time-weighted CO exposure. Isoflurane significantly increased cytochrome c peroxidase activity, cytochrome c release, the number of activated caspase-3 cells, and TUNEL positive nuclei in the forebrain of air-exposed mice. CO, however, abrogated isoflurane-induced cytochrome c peroxidase activation and cytochrome c release from forebrain mitochondria and decreased the number of activated caspase-3 positive cells and TUNEL positive nuclei after simultaneous exposure with isoflurane. Taken together, the data indicate that CO can limit apoptosis after isoflurane exposure via inhibition of cytochrome c peroxidase depending on concentration. Although it is unknown whether CO directly inhibited isoflurane-induced apoptosis, it is possible that low-flow anesthesia designed to target rebreathing of specific concentrations of CO may be a desired strategy to develop in the future in an effort to prevent anesthesia-induced neurotoxicity in infants and children.


Tregs promote the differentiation of Th17 cells in silica-induced lung fibrosis in mice.
Silicosis is an occupational lung disease caused by inhalation of silica dust and characterized by lung inflammation and fibrosis. Previous study showed that Tregs regulate the process of silicosis by modulating the maintenance of immune homeostasis in the lung. Th17 cells share reciprocal developmental pathway with Tregs and play a pivotal role in the immunopathogenesis of many lung diseases by recruiting and activating neutrophils, but the regulatory function of Tregs on Th17 response in silica induced lung fibrosis remains to be explored. To evaluate the role of Th17 and IL-17 in the development of silicosis and their interaction with Tregs, Treg-depleted mice model was generated and exposed to silica to establish experimental model of silica-induced lung fibrosis. Here we showed that silica increased Th17 response in lung fibrosis. Tregs depletion enhanced the neutrophils accumulation and attenuated Th17 response in silica induced lung fibrosis. Both mRNA and protein results showed that Tregs exerted its modulatory function on Th17 cells and IL-17 by regulating TGF-β1 and IL-1β. Our study suggested that Tregs could promote Th17 cells differentiation by regulating TGF-β1 and IL-1β in silica induced lung fibrosis of mice, which further the understanding of the progress of silicosis and provide a new insight in the regulatory mechanism of Th17 by Tregs in lung inflammation.


Transcription factors Runx1 to 3 are expressed in the lacrimal gland epithelium and are involved in regulation of gland morphogenesis and regeneration.
Lacrimal gland (LG) morphogenesis and repair are regulated by a complex interplay of intrinsic factors (e.g., transcription factors) and extrinsic signals (e.g., soluble growth/signaling factors). Many of these interconnections remain poorly characterized. Runt-related (Runx) factors belong to a small family of heterodimeric transcription factors known to regulate lineage-specific proliferation and differentiation of stem cells. The purpose of this study was to define the expression pattern and the role of Runx proteins in LG development and regeneration. Expression of epithelial-restricted transcription factors in murine LG was examined using immunostaining, qRT-PCR, and RT(2)Profiler PCR microarrays. The role of Runx transcription factors in LG morphogenesis was studied using siRNA and ex vivo LG cultures. Expression of Runx transcription factors during LG regeneration was assessed using in vivo model of LG regeneration. We found that Runx factors are expressed in the epithelial compartment of the LG; in particular, Runx1 was restricted to the epithelium with highest level of expression in ductal and centroacinar cells. Downregulation of Runx1 to 3 expression using Runx-specific siRNAs abolished LG growth and branching and our data suggest that Runx1, 2, and 3 are partially redundant in LG development. In siRNA-treated LG, reduction of branching correlated with reduction of epithelial proliferation, as well as expression of cyclin D1 and the putative epithelial progenitor cell marker cytokeratin-5. Runx1, Runx3, and cytokeratin-5 expression increased significantly in regenerating LG and there was modest increase in Runx2 expression during LG differentiation. Runx1 and 2 are new markers of the LG epithelial lineage and Runx factors are important for normal LG morphogenesis and regeneration.


Nod-like receptors in intestinal homeostasis, inflammation, and cancer.
NLRs have been shown in a number of models to protect against microbial infection through their ability to participate in "pattern recognition" and their triggering of inflammatory pathways to control infection. Over the past few years, however, the role of NLRs, especially Nod1, Nod2, and NLRP3, in intestinal homeostasis has been highlighted. Indeed, these specific NLRs have been implicated in IBD, in particular, the association of Nod2 with CD, yet a clear understanding of how dysfunctional NLR activation leads to aberrant inflammation is still the focus of much investigation. In this review, we will examine how NLRs participate in the maintenance of gut homeostasis and how upset of this regulation can tip the balance toward chronic inflammation and intestinal cancer.