Bone mineral density and fractures in boys with Duchenne muscular dystrophy.
The relationships between bone density, mobility, and fractures were assessed in 41 boys with Duchenne muscular dystrophy. Bone density in the lumbar spine was only slightly decreased while the boys were ambulatory (mean z-score, -0.8), but significantly decreased with loss of ambulation (mean z-score, -1.7). In contrast, bone density in the proximal femur was profoundly diminished even when gait was minimally affected (mean z-score, -1.6), and then progressively decreased to nearly 4 standard deviations below age-matched normals (mean z-score, -3.9). These are consistent with the findings that 18 (44%) of the boys sustained a fracture, 66% of these fractures involved the lower extremities, and there were no spinal compression fractures. Furthermore, four (44%) of nine boys who were walking with aids or support at the time of fracture never resumed walking after the fracture. Osteoporosis is most profound in the lower extremities of boys with Duchenne muscular dystrophy, and begins to develop early while still ambulating. Frequent fractures that may result in loss of ambulation are the clinical consequences.


Tart Cherry Increases Lifespan in Caenorhabditis elegans by Altering Metabolic Signaling Pathways.
Aging and healthspan are determined by both environmental and genetic factors. The insulin/insulin-like growth factor-1(IGF-1) pathway is a key mediator of aging in Caenorhabditis elegans and mammals. Specifically, DAF-2 signaling, an ortholog of human IGF, controls DAF-16/FOXO transcription factor, a master regulator of metabolism and longevity. Moreover, mitochondrial dysfunction and oxidative stress are both linked to aging. We propose that daily supplementation of tart cherry extract (TCE), rich in anthocyanins with antioxidant properties may exert dual benefits for mitochondrial function and oxidative stress, resulting in beneficial effects on aging in C. elegans. We found that TCE supplementation at 6 μg or 12 μg/mL, increased (p < 0.05) the mean lifespan of wild type N2 worms, respectively, when compared to untreated control worms. Consistent with these findings, TCE upregulated (p < 0.05) expression of longevity-related genes such as daf-16 and aak-2 (but not daf-2 or akt-1 genes) and genes related to oxidative stress such as sod-2. Further, we showed that TCE supplementation increased spare respiration in N2 worms. However, TCE did not change the mean lifespan of daf-16 and aak-2 mutant worms. In conclusion, our findings indicate that TCE confers healthspan benefits in C. elegans through enhanced mitochondrial function and reduced oxidative stress, mainly via the DAF-16 pathway.


Chronic pain diagnosis in refugee torture survivors: A prospective, blinded diagnostic accuracy study.
An estimated 87% of torture survivors experience chronic pain such as brachial plexopathy from upper extremity suspension or lumbosacral plexus injury from leg hyperextension. However, a vast majority of pain is undetected by evaluators due to a lack of diagnostic tools and confounding psychiatric illness. This diagnostic gap results in exclusive psychological treatment rather than multimodal therapies, substantially limiting rehabilitation. We hypothesized that the United Nations Istanbul Protocol (UNIP) would have a sensitivity of approximately 15% for pain detection, and that the use of a validated pain screen would improve its sensitivity by at least 29%, as compared to the reference standard (pain specialist evaluation). This prospective blind-comparison-to-gold-standard study of survivors of torture, as defined by the World Medical Association, took place at Weill Cornell Medicine between February 1, 2017, and June 21, 2019. 11 women and 9 men, for a total of 20 participants, were included in the analysis. Five participants received 2 UNIP evaluations, for a total of 25 unique evaluations included in the analysis. Participants were representative of a global population, with home countries in Africa, Central America, South Asia, the Caribbean, and the Middle East. Methods of torture experienced were homogeneous, following the predictable pattern of systematic torture. Participants first received the standard evaluation protocol for torture survivors (UNIP) by a trained evaluator, and subsequently received a validated pain screen (Brief Pain Inventory-Short Form [BPISF]) followed by a noninvasive examination by a pain specialist physician (reference standard). The primary outcome was the diagnostic and treatment capability of the standard protocol (index test) versus the validated pain screen (BPISF), as compared to the reference standard. Trained evaluators performing the initial assessment with the UNIP (index test) were blinded to the study, and the pain specialist physician (reference standard) was blinded to the outcome of the initial UNIP evaluation and the BPISF; data from the initial UNIP assessment were not gathered by the principal investigator until all other study procedures were completed. Providers using only the UNIP captured pain in a maximum of 16% of evaluations, as compared to 85% of participants being diagnosed with pain by the reference standard. When employed, the validated pain screen had a sensitivity of 100% (95% CI 72%-100%) and a negative predictive value of 100%, as compared to a sensitivity of 24% (95% CI 8%-50%) and a negative predictive value of 19% (95% CI 5%-46%) for the index test. The difference in the sensitivity of the UNIP as compared to the BPISF was significant, with p < 0.001. No adverse events owing to participation in the study were reported by participants. Limitations of the study include small sample size, its single-site nature, and the exclusion of individuals who did not speak 1 of the 5 study languages. These data indicate that a validated pain screen can supplement the current global standard assessment of torture survivors, the UNIP, to increase the accuracy of pain diagnosis. ClinicalTrials.gov NCT03018782.


Medicare part D data: major changes on the horizon.
The 3 primary administrative data sets developed by the Centers for Medicare and Medicaid services (CMS) to support the Medicare Part D program implementation represent a valuable source of data for health services researchers. This paper describes the structure of the Medicare Part D program and the related databases, and discusses their utilization for research purposes. The Medicare Part D administrative data include information on plan benefits (integrated into the Health Plan Management System), beneficiary enrollment files, and prescription drug event (PDE) claims-type data. The enrollment data may be of use in investigating the benefits and plan types that appeal to beneficiaries, but their application is limited by the fact that, although individual beneficiaries' enrollment choices are recorded, only summary enrollment data are currently publicly available. PDE data are likely to be of most interest to researchers as they are detailed (including beneficiary identifiers, contract identifiers pharmacy provider information on drugs provided, drug cost, and insurance status), beneficiary-specific (allowing them to be linked to beneficiary characteristics), and an unusual output for a program reimbursed under a capitation-based system. Because PDE data are highly sensitive, only summary data on the number of Part D prescriptions filled are publicly available. Although the data collected in relation to the Medicare Part D program could be applied to many questions of interest to health services researchers, their utility is limited by the sensitive natures of many of these data, making it difficult currently to obtain access for research purposes.


Halloysite Nanocapsules Containing Thyme Essential Oil: Preparation, Characterization, and Application in Packaging Materials.
Halloysite nanotubes (HNTs), which are natural nanomaterials, have a hollow tubular structure with about 15 nm inner and 50 nm outer diameters. Because of their tubular shape, HNTs loaded with various materials have been investigated as functional nanocapsules. In this study, thyme essential oil (TO) was encapsulated successfully in HNTs using vacuum pulling methods, followed by end-capping or a layer-by-layer surface coating process for complete encapsulation. Nanocapsules loaded with TO were mixed with flexographic ink and coated on a paper for applications as food packaging materials. Scanning electron microscopy and transmission electron microscopy were used to characterize the morphology of the nanocapsules and to confirm the TO loading of the nanocapsules. Fourier transform infrared spectroscopy and thermogravimetric analyses analysis were used to complement the structural information. In addition, the controlled release of TO from the nanocapsules showed sustained release properties over a period of many days. The results reveal that the release properties of TO in these nanocapsules could be controlled by surface modifications such as end-capping and/or surface coating of bare nanocapsules. The packaging paper with TO-loaded HNT capsules was effective in eliminating against Escherichia coli during the first 5 d and showed strong antibacterial activity for about 10 d.


Iatrosophia and an eighteenth-century oneirokritēs in the National Library of Greece.
Medical dreams were not discussed by Greek popular dream interpreters, but were the domain of physicians like Hippocrates, Galen, and Rufus of Ephesus, or the followers of the healing god Asclepius. An exception is an oneirokrites (dreambook) in Codex 1350 of the National Library of Greece in Athens. This eighteenth-century text reflects Ottoman Greek iatrosophia. An iatrosophion, widely used in Byzantine and Ottoman Greece, was a physician's notebook of recipes and treatments or was the collective compendium of classical and Byzantine medical and pharmacological texts consulted in hospital settings. Some iatrosophia included medical cures and drugs, but also spells, exorcisms, magic, astrology, and practical advice. The writer of our oneirokrites used such a magico-medical iatrosophion. After interpreting a dream symbol, he often advises a prophylactic (usually dietary) cure or treatment for restoring or maintaining health, or recommends religious prayers and spells, or apotropaic magic.


Reversal of schizophrenia-like symptoms and immune alterations in mice by immunomodulatory drugs.
Immune dysregulation observed in schizophrenia alters tryptophan metabolism. Tryptophan metabolism is triggered by indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). Tryptophan is converted to quinolinic acid, a potent neurotoxin, and to kynurenic acid, an NMDA antagonist. 1-Methyl-D-tryptophan (MDT) inhibits IDO. Melatonin is metabolized by IDO while inhibiting TDO. We evaluated the reversal of ketamine-induced schizophrenia-like behavioral and neurochemical alterations in mice by the administration of MDT (20 or 40 mg/kg, i.p.) or melatonin (15 mg/kg, per os). Oxidative stress and inflammatory alterations, i.e. myeloperoxidase activity (MPO), reduced glutathione (GSH), lipid peroxidation (LPO) and interleukin (IL)-4 and IL-6 were measured in the prefrontal cortex (PFC), hippocampus and striatum. Risperidone was used as standard antipsychotic. Ketamine triggered positive- (PPI deficits and hyperlocomotion), cognitive- (working memory deficits) and negative (social interaction deficits) schizophrenia-like symptoms. These symptoms were accompanied by increased MPO activity, decreased GSH and increased LPO in all brain areas and increments in hippocampal IL-4 and IL-6. MDT and melatonin reversed all ketamine-induced behavioral alterations. Risperidone did not reverse working memory deficits. MDT and melatonin reversed alterations in MPO activity and GSH levels. LP was reversed only by melatonin and risperidone. Risperidone could not reverse MPO alterations in the PFC and striatum. All drugs reversed the alterations in IL-4 and IL-6. The hippocampus and striatum of ketamine+melatonin-treated animals had lower levels of IL-6. Our findings provide further preclinical evidence that immune-inflammatory and oxidative pathways are involved in schizophrenia and that targeting these pathways is a valid treatment option in schizophrenia.


Rapid detection of Staphylococcus aureus and methicillin resistance in bone and joint infection samples: evaluation of the GeneXpert MRSA/SA SSTI assay.
The GeneXpert MRSA/SA SSTI assay was compared to conventional cultures to detect Staphylococcus aureus and methicillin-resistance from 91 bone and joint infection samples. Sensitivity and specificity were 94.4% and 100%. Three false-positive results were observed, in fact providing from patients known to be infected by S. aureus on the basis of other concomitant osteoarticular samples, which suggests that PCR was more sensitive than culture. This diagnosis accuracy may help shorten toxic and non-optimal empirical therapies such as glycopeptides in case of methicillin-susceptible strains.


Molecularly imprinted polymer nanoparticle-based assay (MINA): application for fumonisin B1 determination.
The enzyme-linked immunosorbent assay (ELISA) has been used as a standard tool for monitoring food and animal feed contamination from the carcinogenic fumonisin B1 (FB1). Unfortunately, ELISA is not always efficient due to the instability of the antibody and enzyme components in the immunoassay, the presence of natural enzyme inhibitors in the samples and the high levels of non-specific protein binding. Additionally, the production of antibodies for ELISA can be time-consuming and costly, due to the involvement of animals in the manufacturing process. To overcome these limiting factors, a molecularly imprinted nanoparticle based assay (MINA) has been developed, where the molecularly imprinted nanoparticles (nanoMIPs) replace the primary antibody used in a competitive ELISA. Herein, computational modelling was used to design the nanoMIPs by selecting monomers that specifically interact with FB1. The affinity of the monomers to FB1 was verified by measuring their binding in affinity chromatography experiments. The nanoMIPs were produced by solid phase synthesis and the results showed that nanoMIPs had a hydrodynamic diameter of around 249 ± 29 nm. The assay tested in model samples is highly selective and does not show cross-reactivity with other mycotoxins such as fumonisin B2 (FB2), aflatoxin B1 (AFB1), citrinin (CTT), zearalenone (ZEA), and deoxynivalenol (DON). The MINA allows the detection of FB1 in the concentration range of 10 pM-10 nM with a detection limit of 1.9 pM and a recovery of 108.13-113.76%.


A chemical mismatch cleavage method useful for the detection of point mutations in the p53 gene in lung cancer.
Point mutations in genes can be etiologic of pulmonary diseases, as in the case of the inherited disorders alpha-1-antitrypsin deficiency and cystic fibrosis or in the context of dominant and recessive oncogenes in lung cancer. Various methodologies have been developed to screen for single-base mutations. These techniques include direct DNA sequencing, RNase protection, denaturing gradient gel electrophoresis, and chemical mismatch cleavage. The latter method offers the advantages of rapid and efficient analysis of genomic or cDNA and is thus ideally suited to screening applications. Furthermore, all possible single-base changes can theoretically be detected. In the present work, chemical mismatch cleavage was utilized to detect mutations in the p53 gene in small cell and non-small cell lung cancer. This technique was modified by using a two-step, hemi-nested PCR procedure for preparation of target genomic DNAs permitting an expanded target size for analysis. Evaluation by chemical mismatch cleavage of eight p53 cDNAs derived from lung tumors shown to have different mutations by DNA sequencing correctly detected the presence of a point mutation in all instances. Analysis of six additional tumor genomic DNAs with defined mutations in the corresponding p53 cDNAs accurately confirmed the mutation at the level of the genome. The technique also identified codon 72 and intron 6 polymorphisms. Using the intron 6 polymorphism, loss of heterozygosity at the p53 locus in tumor DNA was readily detected by chemical mismatch cleavage. Finally, utilizing this technique for scanning analysis of the p53 gene of uncharacterized lung tumor DNAs, additional mutations were identified in a prospective manner which were confirmed by sequence analysis.(ABSTRACT TRUNCATED AT 250 WORDS)


Molecular identification of Mucorales in human tissues: contribution of PCR electrospray-ionization mass spectrometry.
Molecular methods are crucial for mucormycosis diagnosis because cultures are frequently negative, even if microscopy suggests the presence of hyphae in tissues. We assessed PCR/electrospray-ionization mass spectrometry (PCR/ESI-MS) for Mucorales identification in 19 unfixed tissue samples from 13 patients with proven or probable mucormycosis and compared the results with culture, quantitative real-time PCR, 16S-23S rRNA gene internal transcribed spacer region (ITS PCR) and 18S PCR sequencing. Concordance with culture identification to both genus and species levels was higher for PCR/ESI-MS than for the other techniques. Thus, PCR/ESI-MS is suitable for Mucorales identification, within 6 hours, for tissue samples for which microscopy results suggest the presence of hyphae.


Entamoeba histolytica: a eukaryote without glutathione metabolism.
Entamoeba histolytica was found to grow normally without producing glutathione and the main enzymes of glutathione metabolism, indicating that glutathione is not essential for many eukaryotic processes. This parasitic amoeba is an unusual eukaryote whose special features may help define the crucial functions of glutathione in those eukaryotes that do use it. Since Entamoeba histolytica lacks mitochondria and the usual aerobic respiratory pathways, the finding that it grows without glutathione and other evidence support the hypothesis that a primary function of glutathione in eukaryotes involves protection against oxygen toxicity associated with mitochondria and suggest that eukaryotes may have acquired glutathione metabolism at the time that they acquired mitochondria.


Preclinical efficacy of hK2 targeted [177Lu]hu11B6 for prostate cancer theranostics.
Androgen ablating drugs increase life expectancy in men with metastatic prostate cancer, but resistance inevitably develops. In a majority of these recurrent tumors, the androgen axis is reactivated in the form of increased androgen receptor (AR) expression. Targeting proteins that are expressed as a down-stream effect of AR activity is a promising rationale for management of this disease. The humanized IgG1 antibody hu11B6 internalizes into prostate and prostate cancer (PCa) cells by binding to the catalytic cleft of human kallikrein 2 (hK2), a prostate specific enzyme governed by the AR-pathway. In a previous study, hu11B6 conjugated with Actinium-225 (225Ac), a high linear energy transfer (LET) radionuclide, was shown to generate an AR-upregulation driven feed-forward mechanism that is believed to enhance therapeutic efficacy. We assessed the efficacy of hu11B6 labeled with a low LET beta-emitter, Lutetium-177 (177Lu) and investigated whether similar tumor killing and AR-enhancement is produced. Moreover, single-photon emission computed tomography (SPECT) imaging of 177Lu is quantitatively accurate and can be used to perform treatment planning. [177Lu]hu11B6 therefore has significant potential as a theranostic agent. Materials and Methods: Subcutaneous PCa xenografts (LNCaP s.c.) were grown in male mice. Biokinetics at 4-336 h post injection and uptake as a function of the amount of hu11B6 injected at 72 h were studied. Over a 30 to 120-day treatment period the therapeutic efficacy of different activities of [177Lu]hu11B6 were assessed by volumetric tumor measurements, blood cell counts, molecular analysis of the tumor as well as SPECT/CT imaging. Organ specific mean absorbed doses were calculated, using a MIRD-scheme, based on biokinetic data and rodent specific S-factors from a modified MOBY phantom. Tumor tissues of treated xenografts were immunohistochemically (IHC) stained for Ki-67 (proliferation) and AR, SA-β-gal activity (senescence) and analyzed by digital autoradiography (DAR). Results: Organ-to-blood and tumor-to-blood ratios were independent of hu11B6 specific activity except for the highest amount of antibody (150 µg). Tumor accumulation of [177Lu]hu11B6 peaked at 168 h with a specific uptake of 29 ± 9.1 percent injected activity per gram (%IA/g) and low accumulation in normal organs except in the submandibular gland (15 ± 4.5 %IA/g), attributed to a cross-reaction with mice kallikreins in this organ, was seen. However, SPECT imaging with therapeutic amounts of [177Lu]hu11B6 revealed no peak in tumor accumulation at 7 d, probably due to cellular retention of 177Lu and decreasing tumor volumes. For [177Lu]hu11B6 treated mice, tumor decrements of up to 4/5 of the initial tumor volume and reversible myelotoxicity with a nadir at 12 d were observed after a single injection. Tumor volume reduction correlated with injected activity and the absorbed dose. IHC revealed retained expression of AR throughout treatment and that Ki-67 staining reached a nadir at 9-14 d which coincided with high SA- β-gal activity (14 d). Quantification of nuclei staining showed that Ki-67 expression correlated negatively with activity uptake. AR expression levels in cells surviving therapy compared to previous timepoints and to controls at 30 d were significantly increased (p = 0.017). Conclusions: This study shows that hu11B6 labeled with the low LET beta-emitting radionuclide 177Lu can deliver therapeutic absorbed doses to prostate cancer xenografts with transient hematological side-effects. The tumor response correlated with the absorbed dose both on a macro and a small scale dosimetric level. Analysis of AR staining showed that AR protein levels increased late in the study suggesting a therapeutic mechanism, a feed forward mechanism coupled to AR driven response to DNA damage or clonal lineage selection, similar to that reported in high LET alpha-particle therapy using 225Ac labeled hu11B6, however emerging at a later timepoint.


Enantioselective Synthesis of Allenes by Catalytic Traceless Petasis Reactions.
Allenes are useful functional groups in synthesis as a result of their inherent chemical properties and established reactivity patterns. One property of chemical bonding renders 1,3-substituted allenes chiral, making them attractive targets for asymmetric synthesis. While there are many enantioselective methods to synthesize chiral allenes from chiral starting materials, fewer methods exist to directly synthesize enantioenriched chiral allenes from achiral precursors. We report here an asymmetric boronate addition to sulfonyl hydrazones catalyzed by chiral biphenols to access enantioenriched allenes in a traceless Petasis reaction. The resulting Mannich product from nucleophilic addition eliminates sulfinic acid, yielding a propargylic diazene that performs an alkyne walk to afford the allene. Two enantioselective approaches have been developed; alkynyl boronates add to glycolaldehyde imine to afford allylic hydroxyl allenes, and allyl boronates add to alkynyl imines to form 1,3-alkenyl allenes. In both cases, the products are obtained in high yields and enantioselectivities.


Analysis of whistles produced by the Tucuxi Dolphin Sotalia fluviatilis from Sepetiba Bay, Brazil.
From July 2001 to June 2002, we recorded a total of 2 h 55 min of Tucuxi Dolphin Sotalia fluviatilis vocalizations from Sepetiba Bay, Brazil (22 degrees 35'S-44 degrees 03'W). A total of 3350 whistles were analyzed quantitative and qualitatively and were divided into 124 types, by visual inspection of sonograms. The following parameters were measured: Initial Frequency, Final Frequency, Minimum Frequency, Maximum Frequency, Duration, Number of Inflections, Frequency at the Inflection Points, Frequency at 1/2, 1/4, and 3/4 of whistle duration, Presence of Frequency Modulation and Harmonics. Ascending type whistles (N = 2719) were most common, representing 82% of the total. Dolphin behavior and average group size observed during recording influenced the whistle's quantitative and qualitative parameters. The results demonstrate the great diversity of whistles emitted and indicate a functional role of these vocalizations during the observed behaviors.


Periodic actin structures in neuronal axons are required to maintain microtubules.
Axons are cable-like neuronal processes wiring the nervous system. They contain parallel bundles of microtubules as structural backbones, surrounded by regularly spaced actin rings termed the periodic membrane skeleton (PMS). Despite being an evolutionarily conserved, ubiquitous, highly ordered feature of axons, the function of PMS is unknown. Here we studied PMS abundance, organization, and function, combining versatile Drosophila genetics with superresolution microscopy and various functional readouts. Analyses with 11 actin regulators and three actin-targeting drugs suggest that PMS contains short actin filaments that are depolymerization resistant and sensitive to spectrin, adducin, and nucleator deficiency, consistent with microscopy-derived models proposing PMS as specialized cortical actin. Upon actin removal, we observed gaps in microtubule bundles, reduced microtubule polymerization, and reduced axon numbers, suggesting a role of PMS in microtubule organization. These effects become strongly enhanced when carried out in neurons lacking the microtubule-stabilizing protein Short stop (Shot). Combining the aforementioned actin manipulations with Shot deficiency revealed a close correlation between PMS abundance and microtubule regulation, consistent with a model in which PMS-dependent microtubule polymerization contributes to their maintenance in axons. We discuss potential implications of this novel PMS function along axon shafts for axon maintenance and regeneration.


Reduced flight-to-light behaviour of moth populations exposed to long-term urban light pollution.
The globally increasing light pollution is a well-recognized threat to ecosystems, with negative effects on human, animal and plant wellbeing. The most well-known and widely documented consequence of light pollution is the generally fatal attraction of nocturnal insects to artificial light sources. However, the evolutionary consequences are unknown. Here we report that moth populations from urban areas with high, globally relevant levels of light pollution over several decades show a significantly reduced flight-to-light behaviour compared with populations of the same species from pristine dark-sky habitats. Using a common garden setting, we reared moths from 10 different populations from early-instar larvae and experimentally compared their flight-to-light behaviour under standardized conditions. Moths from urban populations had a significant reduction in the flight-to-light behaviour compared with pristine populations. The reduced attraction to light sources of 'city moths' may directly increase these individuals' survival and reproduction. We anticipate that it comes with a reduced mobility, which negatively affects foraging as well as colonization ability. As nocturnal insects are of eminent significance as pollinators and the primary food source of many vertebrates, an evolutionary change of the flight-to-light behaviour thereby potentially cascades across species interaction networks.


Clinical features and prognosis of late-onset systemic lupus erythematosus: results from the 1000 faces of lupus study.
There is controversy whether older-onset systemic lupus erythematosus (SLE) is associated with a different, more benign disease course than in younger-onset SLE. Our objective was to characterize the clinical features and prognosis of late-onset SLE in a large, multicenter cohort. We studied adult-onset lupus in the 1000 Canadian Faces of Lupus cohort (n = 1528) of whom 10.5% had onset at age > or = 50 years versus a control group with onset at < 50 years. Disease duration was different in early- and late-onset groups (15 yrs in early vs 9.3 yrs in late; p < 0.001). Caucasians were represented more in the later-onset SLE group (55.6% vs 74.5%), while Asians and Blacks were more prevalent in the younger group. Younger-onset SLE subjects fulfilled more American College of Rheumatology criteria for SLE (< 50 yrs: 5.98 +/- 1.68; > or = 50 yrs: 5.24 +/- 1.44; p < 0.0001). Despite an equal prevalence of anti-dsDNA, the younger-onset group more often had positive anti-Smith autoantibody, ribonucleoprotein, and hypocomplementemia, and more nephritis, rash, and cytopenias than the older-onset group. However, disease activity and damage accrual were higher in the older-onset group. The older patients received less prednisone and immunosuppressives (current and ever-use). As expected, comorbidity was higher in the older-onset SLE group. This study suggests that older age-onset SLE is not benign. There may be an interaction between lupus and age in which, although there is less lupus nephritis in the elderly, more disease activity and damage are present.


Both Lewis and secretor status mediate susceptibility to rotavirus infections in a rotavirus genotype-dependent manner.
The live oral rotavirus (RV) vaccines have shown a reduced efficacy in Africa. Recent in vitro studies have shown binding of the RV surface protein (VP4) to histo-blood group antigens (HBGAs) in an RV genotype-dependent manner, suggesting them to be putative receptors for RV. The diversity of HBGA phenotypes in different ethnic populations, combined with prevalence/absence of specific RV genotypes, led us to hypothesize whether the genetic variations in HBGAs in a population limit susceptibility to certain RV genotypes, plausibly leading to reduced vaccine efficacy. Association between HBGAs status and susceptibility to RV P genotypes was investigated in children in Burkina Faso and Nicaragua. In total, 242 children with diarrhea in Burkina Faso and Nicaragua were investigated, 93 of whom were RV positive. In Burkina Faso, the P[8] RV strains (n = 27) infected only Lewis- and secretor-positive children (27/27; P < .0001), but no Lewis-negative children. In contrast, the P[6] strains (n = 27) infected predominantly Lewis-negative children (n = 18; P < .0001) but also Lewis-positive children, irrespective of their secretor status. The results from Nicaragua confirmed that all P[8]-infected children (n = 22) were secretor Lewis positive. As VP4 of genotype P[8] is a component of current RV vaccines, our finding that Lewis-negative children are resistant to P[8] strains provides a plausible explanation for the reduced vaccine efficacy in populations with a high percentage of Lewis-negative individuals, such as in Africa. Furthermore, our findings provide a plausible explanation as to why P[6] RV strains are more common in Africa.


Cross-national time trends in bullying behaviour 1994-2006: findings from Europe and North America.
To identify trends over 12 years in the prevalence of bullying and associated victimization among adolescents in North American and European countries. Cross-sectional self-report surveys were obtained from nationally representative samples of 11-15 year old school children in 21 countries in 1993/94 and in 27 countries in each of 1997/98, 2001/02 and 2005/06. Measures included involvement in bullying as either a perpetrator and/or victim. Consistent decreases in the prevalence of bullying were reported between 1993/94 to 2005/06 in most countries. Geographic patterns show consistent decreases in bullying in Western European countries and in most Eastern European countries. An increase or no change in prevalence was evident in almost all English speaking countries participating in the study (England, Scotland, Wales, Ireland and Canada, but not in the USA). Study findings demonstrated a significant decrease in involvement in bullying behaviour in most participating countries. This is encouraging news for policy-makers and practitioners working in the field of bullying prevention.


A streptococcal effector protein that inhibits Porphyromonas gingivalis biofilm development.
Dental plaque formation is a developmental process involving cooperation and competition within a diverse microbial community, approximately 70 % of which is composed of an array of streptococci during the early stages of supragingival plaque formation. In this study, 79 cell-free culture supernatants from a variety of oral streptococci were screened to identify extracellular compounds that inhibit biofilm formation by the oral anaerobe Porphyromonas gingivalis strain 381. The majority of the streptococcal supernatants (61 isolates) resulted in lysis of P. gingivalis cells, and some (17 isolates) had no effect on cell viability, growth or biofilm formation. One strain, however, produced a supernatant that abolished biofilm formation without affecting growth rate. Analysis of this activity led to the discovery that a 48 kDa protein was responsible for the inhibition. Protein sequence identification and enzyme activity assays identified the effector protein as an arginine deiminase. To identify the mechanism(s) by which this protein inhibits biofilm formation, we began by examining the expression levels of genes encoding fimbrial subunits; surface structures known to be involved in biofilm development. Quantitative RT-PCR analysis revealed that exposure of P. gingivalis cells to this protein for 1 h resulted in the downregulation of genes encoding proteins that are the major subunits of two distinct types of thin, single-stranded fimbriae (fimA and mfa1). Furthermore, this downregulation occurred in the absence of arginine deiminase enzymic activity. Hence, our data indicate that P. gingivalis can sense this extracellular protein, produced by an oral streptococcus (Streptococcus intermedius), and respond by downregulating expression of cell-surface appendages required for attachment and biofilm development.


[The antioxidant function of high density lipoproteins: a new paradigm in atherosclerosis].
The one disease associated with the greatest morbidity and mortality in industrialized countries is coronary heart disease (CHD). High density lipoprotein (HDL) is one of the most important independent protective factors for the arteriosclerosis which underlies CHD. Paraoxonase 1 (PON1) is an enzyme that confers antioxidant properties to HDL. In vitro, PON1 hydrolyzes a large variety of endogenous or exogenous substrates, some of which are clearly involved in the progression of arteriosclerosis. A close relationship between PON1 deficiency and accelerated progression of arteriosclerosis has been found in animal models. Moreover, PON1 activity is reduced in high oxidative stress diseases such as CHD, dyslipoproteinemias, inflammatory processes, diabetes and certain neuropathies. Reduced PON1 enzyme activity is associated with several arteriosclerosis-related diseases. The most thoroughly studied genetic variant of PON1 is PON1-192, in which the R allele is associated with elevated paraoxonase activity. This allele, present in 24.8% of the Italian population, is found in up to 78.9% of the population of Ecuadorian Cayapa Indians. A metaanalysis of studies on the relationship between CHD and the R allele showed the latter to be an independent risk factor for this disease, with an odds ratio of 1.18 (95% confidence interval, 1.10-1.27). The PON1 enzyme is a potentially useful new qualitative indicator in addition to the well known reverse cholesterol transport capacity associated with high plasma levels of HDL.


Strategies to promote family-professional collaboration: two case reports.
Although research supports family-professional collaboration, challenges to implementation have been reported. The case reports describe the implementation of a 4-step practice model that incorporates specific strategies to facilitate family-professional collaboration. The participants were two mothers of children with physical disabilities and two physical therapists. Therapists received instruction in the strategies for collaboration including client-centred interview, visualising a preferred future, scaling questions, and family routine and activity matrix. The intervention was implemented during 6-weekly sessions. The 2nd and 5th sessions were videotaped to analyse the interactions between the parent and therapist using Response Class Matrix. Telephone interviews were conducted to explore participants' experiences. Therapists were able to implement all strategies following 6 h of instruction. Analysis of the videotapes indicated that mother-therapist interactions were characterised by sharing information and open communication in a mutually supportive manner. Interviews with the mothers and therapists indicated that the therapists engaged the mothers in the intervention process and tailored interventions to child and family needs. The scaling questions were difficult to implement (therapists) and answer (parents). The findings suggest that the strategies can be used by therapists to promote collaboration and involve parents in setting goals and the intervention process. Implications for Rehabilitation Strategies to promote parent-therapist collaboration include client-centred interview, visualising a preferred future, scaling questions, and family routine and activity matrix. Therapists with no previous instruction or training on family-centred services successfully implemented the strategies following 6 h of instruction. Interactions between two parent-physical therapist dyads were characterised by sharing information and open communication in a mutually supportive manner following therapist instruction in strategies for parent-therapist collaboration.


Diagnostic approach for monitoring hydroclimatic conditions related to emergence of west nile virus in west virginia.
West Nile virus (WNV), mosquito-borne and water-based disease, is increasingly a global threat to public health. Since its appearance in the northeastern United States in 1999, WNV has since been reported in several states in the continental United States. The objective of this study is to highlight role of hydroclimatic processes estimated through satellite sensors in capturing conditions for emergence of the vectors in historically disease free regions. We tested the hypothesis that an increase in surface temperature, in combination with intensification of vegetation, and enhanced precipitation, lead to conditions favorable for vector (mosquito) growth. Analysis of land surface temperature (LST) pattern shows that temperature values >16°C, with heavy precipitation, may lead to abundance of the mosquito population. This hypothesis was tested in West Virginia where a sudden epidemic of WNV infection was reported in 2012. Our results emphasize the value of hydroclimatic processes estimated by satellite remote sensing, as well as continued environmental surveillance of mosquitoes, because when a vector-borne infection like WNV is discovered in contiguous regions, the risk of spread of WNV mosquitoes increase at points where appropriate hydroclimatic processes intersect with the vector niche.


Dynamics and Distribution of Cyanophages and Their Effect on Marine Synechococcus spp.
Cyanophages infecting marine Synechococcus cells were frequently very abundant and were found in every seawater sample along a transect in the western Gulf of Mexico and during a 28-month period in Aransas Pass, Tex. In Aransas Pass their abundance varied seasonally, with the lowest concentrations coincident with cooler water and lower salinity. Along the transect, viruses infecting Synechococcus strains DC2 and SYN48 ranged in concentration from a few hundred per milliliter at 97 m deep and 83 km offshore to ca. 4 x 10 ml near the surface at stations within 18 km of the coast. The highest concentrations occurred at the surface, where salinity decreased from ca. 35.5 to 34 ppt and Synechococcus concentrations were greatest. Viruses infecting strains SNC1, SNC2, and 838BG were distributed in a similar manner but were much less abundant (<10 to >5 x 10 ml). When Synechococcus concentrations exceeded ca. 10 ml, cyanophage concentrations increased markedly (ca. 10 to > 10 ml), suggesting that a minimum host density was required for efficient viral propagation. Data on the decay rate of viral infectivity d (per day), as a function of solar irradiance I (millimoles of quanta per square meter per second), were used to develop a relationship (d = 0.2610I - 0.00718; r = 0.69) for conservatively estimating the destruction of infectious viruses in the mixed layer of two offshore stations. Assuming that virus production balances losses and that the burst size is 250, ca. 5 to 7% of Synechococcus cells would be infected daily by viruses. Calculations based on contact rates between Synechococcus cells and infectious viruses produce similar results (5 to 14%). Moreover, balancing estimates of viral production with contact rates for the farthest offshore station required that most Synechococcus cells be susceptible to infection, that most contacts result in infection, and that the burst size be about 324 viruses per lytic event. In contrast, in nearshore waters, where ca. 80% of Synechococcus cells would be contacted daily by infectious cyanophages, only ca. 1% of the contacts would have to result in infection to balance the estimated virus removal rates. These results indicate that cyanophages are an abundant and dynamic component of marine planktonic communities and are probably responsible for lysing a small but significant portion of the Synechococcus population on a daily basis.


Precision increase with two orthogonal analyzers in polarization-resolved second-harmonic generation microscopy.
We analyze the increase in precision of parameters estimation for polarization-resolved second-harmonic generation imaging microscopy when two intensities are measured with two orthogonal analyzers. The analysis is performed for measuring anisotropy parameters and molecule orientation for samples with cylindrical symmetry in the presence of photon noise with Poisson statistics. The improvement in comparison to global intensity measurement (i.e., without analyzer) is discussed.


Why do the public support or oppose obesity prevention regulations? Results from a South Australian population survey.
Australian policymakers have acknowledged that implementing obesity prevention regulations is likely to be facilitated or hindered by public opinion. Accordingly, we investigated public views about possible regulations. Cross-sectional survey of 2732 persons, designed to be representative of South Australians aged 15 years and over. Questions examined views about four obesity prevention regulations (mandatory front-of-pack nutrition labelling for packaged foods; zoning restrictions to prohibit fast food outlets near schools; taxes on unhealthy high fat foods; and taxes on sugar-sweetened beverages). Levels of support (Likert scale) for each intervention and reasons for support/opposition were ascertained. Views about the regulations were mixed: support was highest for mandatory nutrition labelling (90%) and lowest for taxes (40%-42%). High levels of support for labelling were generally underpinned by a belief that this regulation would educate "Other" people about nutrition. Lower levels of support for zoning restrictions and taxes were associated with concerns about government overreach and the questionable effectiveness of these regulations in changing behaviours. Levels of support for each regulation, and reasons for support or opposition, differed by gender and socio-economic status. Socio-demographic differences in support appeared to reflect gendered responsibilities for food provision and concerns about the material constraints of socio-economic deprivation. Engagement with target populations may offer insights to optimise the acceptability of regulations and minimise unintended social consequences. SO WHAT?: Resistance to regulations amongst socio-economically disadvantaged target populations warrants attention from public health advocates. Failure to accommodate concerns identified may further marginalise these groups.


Characterization of Schizosaccharomyces pombe mcm7(+) and cdc23(+) (MCM10) and interactions with replication checkpoints.
MCM proteins are required for the proper regulation of DNA replication. We cloned fission yeast mcm7(+) and showed it is essential for viability; spores lacking mcm7(+) begin S phase later than wild-type cells and arrest with an apparent 2C DNA content. We isolated a novel temperature-sensitive allele, mcm7-98, and also characterized two temperature-sensitive alleles of the fission yeast homolog of MCM10, cdc23(+). mcm7-98 and both cdc23ts alleles arrest with damaged chromosomes and an S phase delay. We find that mcm7-98 is synthetically lethal with the other mcmts mutants but does not interact genetically with either cdc23ts allele. However, cdc23-M36 interacts with mcm4ts. Unlike other mcm mutants or cdc23, mcm7-98 is synthetically lethal with checkpoint mutants Deltacds1, Deltachk1, or Deltarad3, suggesting chromosomal defects even at permissive temperature. Mcm7p is a nuclear protein throughout the cell cycle, and its localization is dependent on the other MCM proteins. Our data suggest that the Mcm3p-Mcm5p dimer interacts with the Mcm4p-Mcm6p-Mcm7p core complex through Mcm7p.


Coconut oil is associated with a beneficial lipid profile in pre-menopausal women in the Philippines.
Coconut oil is a common edible oil in many countries, and there is mixed evidence for its effects on lipid profiles and cardiovascular disease risk. Here we examine the association between coconut oil consumption and lipid profiles in a cohort of 1,839 Filipino women (age 35-69 years) participating in the Cebu Longitudinal Health and Nutrition Survey, a community based study in Metropolitan Cebu. Coconut oil intake was estimated using the mean of two 24-hour dietary recalls (9.5±8.9 grams). Lipid profiles were measured in morning plasma samples collected after an overnight fast. Linear regression models were used to estimate the association between coconut oil intake and each plasma lipid outcome after adjusting for total energy intake, age, body mass index (BMI), number of pregnancies, education, menopausal status, household assets and urban residency. Dietary coconut oil intake was positively associated with high density lipoprotein cholesterol especially among pre-menopausal women, suggesting that coconut oil intake is associated with beneficial lipid profiles. Coconut oil consumption was not significantly associated with low density lipoprotein cholesterol or triglyceride values. The relationship of coconut oil to cholesterol profiles needs further study in populations in which coconut oil consumption is common.


FL118, a novel camptothecin derivative, is insensitive to ABCG2 expression and shows improved efficacy in comparison with irinotecan in colon and lung cancer models with ABCG2-induced resistance.
Irinotecan is a camptothecin analogue currently used in clinical practice to treat advanced colorectal cancer. However, acquired resistance mediated by the drug efflux pump ABCG2 is a recognized problem. We reported on a novel camptothecin analogue, FL118, which shows anticancer activity superior to irinotecan. In this study, we sought to investigate the potency of FL118 versus irinotecan or its active metabolite, SN-38, in both in vitro and in vivo models of human cancer with high ABCG2 activity. We also sought to assess the potency and ABCG2 affinity of several FL118 analogues with B-ring substitutions. Colon and lung cancer cells with and without ABCG2 overexpression were treated with FL118 in the presence and absence of Ko143, an ABCG2-selective inhibitor, or alternatively by genetically modulating ABCG2 expression. Using two distinct in vivo human tumor animal models, we further assessed whether FL118 could extend time to progression in comparison with irinotecan. Lastly, we investigated a series of FL118 analogues with B-ring substitutions for ABCG2 sensitivity. Both pharmacological inhibition and genetic modulation of ABCG2 demonstrated that, in contrast to SN-38, FL118 was able to bypass ABCG2-mediated drug resistance. FL118 also extended time to progression in both in vivo models by more than 50% compared with irinotecan. Lastly, we observed that FL118 analogues with polar substitutions had higher affinity for ABCG2, suggesting that the nonpolar nature of FL118 plays a role in bypassing ABCG2-mediated resistance. Our results suggest that in contrast to SN-38 and topotecan, FL118 is a poor substrate for ABCG2 and can effectively overcome ABCG2-mediated drug resistance. Our findings expand the uniqueness of FL118 and support continued development of FL118 as an attractive therapeutic option for patients with drug-refractory cancers resulting from high expression of ABCG2.


Rickets: not a disease of the past.
Rickets develops when growing bones fail to mineralize. In most cases, the diagnosis is established with a thorough history and physical examination and confirmed by laboratory evaluation. Nutritional rickets can be caused by inadequate intake of nutrients (vitamin D in particular); however, it is not uncommon in dark-skinned children who have limited sun exposure and in infants who are breastfed exclusively. Vitamin D-dependent rickets, type I results from abnormalities in the gene coding for 25(OH)D3-1-alpha-hydroxylase, and type II results from defective vitamin D receptors. The vitamin D-resistant types are familial hypophosphatemic rickets and hereditary hypophosphatemic rickets with hypercalciuria. Other causes of rickets include renal disease, medications, and malabsorption syndromes. Nutritional rickets is treated by replacing the deficient nutrient. Mothers who breastfeed exclusively need to be informed of the recommendation to give their infants vitamin D supplements beginning in the first two months of life to prevent nutritional rickets. Vitamin D-dependent rickets, type I is treated with vitamin D; management of type II is more challenging. Familial hypophosphatemic rickets is treated with phosphorus and vitamin D, whereas hereditary hypophosphatemic rickets with hypercalciuria is treated with phosphorus alone. Families with inherited rickets may seek genetic counseling. The aim of early diagnosis and treatment is to resolve biochemical derangements and prevent complications such as severe deformities that may require surgical intervention.


Intravenous tissue-type plasminogen activator for treatment of acute stroke: the Standard Treatment with Alteplase to Reverse Stroke (STARS) study.
Tissue-type plasminogen activator (tPA) is the only therapy for acute ischemic stroke approved by the Food and Drug Administration. To assess the safety profile and to document clinical outcomes and adverse events in patients treated with intravenous tPA for acute stroke in clinical practice. Prospective, multicenter study of consecutive patients enrolled between February 1997 and December 1998 at 57 medical centers in the United States (24 academic and 33 community). Intravenous tPA (recombinant alteplase). Three hundred eighty-nine patients with a mean age of 69 years (range, 28-100 years); 55% were men. Time intervals between stroke symptom onset, hospital arrival, and treatment with tPA; pretreatment computed tomographic scan results, intracerebral hemorrhage, and major systemic bleeding. The modified Rankin Scale score was used to assess clinical outcomes at 30 days. Median time from stroke onset to treatment was 2 hours 44 minutes, and the median baseline National Institutes of Health Stroke Scale score was 13. The 30-day mortality rate was 13%. At 30 days after treatment, 35% of patients had very favorable outcomes (modified Rankin score, 0-1) and 43% were functionally independent (modified Rankin score, 0-2). Thirteen patients (3.3%) experienced symptomatic intracerebral hemorrhage, including 7 who died. Twenty-eight patients (8.2%) had asymptomatic intracerebral hemorrhage within 3 days of treatment with tPA. Protocol violations were reported for 127 patients (32.6%), and included treatment with tPA more than 3 hours after symptom onset in 13.4%, treatment with anticoagulants within 24 hours of tPA administration in 9.3%, and tPA administration despite systolic blood pressure exceeding 185 mm Hg in 6.7%. A multivariate analysis found predictors of favorable outcome to be a less severe baseline National Institutes of Health Stroke Scale score, absence of specific abnormalities (effacement or hypodensity of >33% of the middle cerebral artery territory or a hyperdense middle cerebral artery) on the baseline computed tomographic scan, an age of 85 years or younger, and a lower mean arterial pressure at baseline. This study, conducted at multiple institutions throughout the United States, suggests that favorable clinical outcomes and low rates of symptomatic intracerebral hemorrhage can be achieved using tPA for stroke treatment.


Epigenetic Modifications in T Cells: The Role of DNA Methylation in Salt-Sensitive Hypertension.
The SS (Dahl salt sensitive) rat is an established model of hypertension and renal damage that is accompanied with immune system activation in response to a high-salt diet. Investigations into the effects of sodium-independent and dependent components of the diet were shown to affect the disease phenotype with SS/MCW (JrHsdMcwi) rats maintained on a purified diet (AIN-76A) presenting with a more severe phenotype relative to grain-fed SS/CRL (JrHsdMcwiCrl) rats. Since contributions of the immune system, environment, and diet are documented to alter this phenotype, this present study examined the epigenetic profile of T cells isolated from the periphery and the kidney from these colonies. T cells isolated from kidneys of the 2 colonies revealed that transcriptomic and functional differences may contribute to the susceptibility of hypertension and renal damage. In response to high-salt challenge, the methylome of T cells isolated from the kidney of SS/MCW exhibit a significant increase in differentially methylated regions with a preference for hypermethylation compared with the SS/CRL kidney T cells. Circulating T cells exhibited similar methylation profiles between colonies. Utilizing transcriptomic data from T cells isolated from the same animals upon which the DNA methylation analysis was performed, a predominant negative correlation was observed between gene expression and DNA methylation in all groups. Lastly, inhibition of DNA methyltransferases blunted salt-induced hypertension and renal damage in the SS/MCW rats providing a functional role for methylation. This study demonstrated the influence of epigenetic modifications to immune cell function, highlighting the need for further investigations.


Role of iron in the pathogenesis of Vibrio vulnificus infections.
Infections with Vibrio vulnificus resulting in septicemia and high mortality have been correlated with pre-existing liver disease and hemochromatosis. As these conditions are associated with impaired iron metabolism and as iron availability in the host has been implicated in the pathogenicity of a number of bacterial infections, the role of iron as a possible factor in the pathogenesis of V. vulnificus was examined. Injection of mice with iron resulted in a lowering of the 50% lethal dose from 10(6) to 1.1 cells and in a reduction in the time of death postinfection. Elevated serum iron levels were also produced by damaging livers with injections of CCl4. The inoculum size required to kill these mice was directly correlated with serum iron levels. Since the portal of infection of this organism may be ingestion of contaminated seafood, the effects of iron upon orally induced infection were also studied. The effects of adding iron, transferrin, or Desferal (an iron chelate) upon the growth of V. vulnificus in human and rabbit sera were also examined. Iron appeared to be the limiting factor in the ability of this organism to survive or grow in mammalian sera. These results, both in vitro and in vivo, provided strong evidence that iron may play a major role in the pathogenesis of V. vulnificus.


Technology used to build and transfer mammalian chromosomes.
In the near twenty-year existence of the human and mammalian artificial chromosome field, the technologies for artificial chromosome construction and installation into desired cell types or organisms have evolved with the rest of modern molecular and synthetic biology. Medical, industrial, pharmaceutical, agricultural, and basic research scientists seek the as yet unrealized promise of human and mammalian artificial chromosomes. Existing technologies for both top-down and bottom-up approaches to construct these artificial chromosomes for use in higher eukaryotes are very different but aspire to achieve similar results. New capacity for production of chromosome sized synthetic DNA will likely shift the field towards more bottom-up approaches, but not completely. Similarly, new approaches to install human and mammalian artificial chromosomes in target cells will compete with the microcell mediated cell transfer methods that currently dominate the field.


Appropriate Minimal Dose of Gadobutrol for 3D Time-Resolved MRA of the Supra-Aortic Arteries: Comparison with Conventional Single-Phase High-Resolution 3D Contrast-Enhanced MRA.
The development of nephrogenic systemic fibrosis and neural tissue deposition is gadolinium dose-dependent. The purpose of this study was to determine the appropriate minimal dose of gadobutrol with time-resolved MRA to assess supra-aortic arterial stenosis with contrast-enhanced MRA as a reference standard. Four hundred sixty-two consecutive patients underwent both standard-dose contrast-enhanced MRA and low-dose time-resolved MRA and were classified into 3 groups; group A (a constant dose of 1 mL for time-resolved MRA), group B (2 mL), or group C (3 mL). All studies were independently evaluated by 2 radiologists for image quality by using a 5-point scale (from 0 = failure to 4 = excellent), grading of arterial stenosis (0 = normal, 1 = mild [<30%], 2 = moderate [30%-69%], 3 = severe to occlusion [≥70%]), and signal-to-noise ratio. The image quality of time-resolved MRA was similar to that of contrast-enhanced MRA in groups B and C, but it was inferior to contrast-enhanced MRA in group A. For the grading of arterial stenosis, there was an excellent correlation between contrast-enhanced MRA and time-resolved MRA (R = 0.957 for group A, R = 0.988 for group B, R = 0.991 for group C). The SNR of time-resolved MRA tended to be lower than that of contrast-enhanced MRA in groups A and B. However, SNR was higher for time-resolved MRA compared with contrast-enhanced MRA in group C. Low-dose time-resolved MRA is feasible in the evaluation of supra-aortic stenosis and could be used as an alternative to contrast-enhanced MRA for a diagnostic technique in high-risk populations.


Basal fuel homoeostasis in symptomatic human immunodeficiency virus infection.
1. In eight clinically stable symptomatic human-immunodeficiency-virus-infected patients and in seven healthy control subjects, glucose and fat metabolism were studied, using indirect calorimetry and primed continuous infusions of [3-3H]glucose and [14C]palmitate. 2. Studies were performed in the post-absorptive state (16 h of overnight fasting) and again after 22 h of overnight fasting. 3. In the post-absorptive state, net fat oxidation and triacylglycerol ('triglyceride') concentrations were significantly higher in the patients, but concentrations and turnover of free fatty acids were not significantly different between patients and control subjects. After 22 h of overnight fasting, free fatty acid turnover in the patients rose to significantly higher levels when compared with the control subjects. 4. Post-absorptive glucose oxidation, glucose turnover and glucose clearance did not differ between patients and control subjects. Although fasting induced a significantly greater decline in glucose turnover in the patients, plasma glucose concentrations decreased comparably in patients and control subjects. 5. No differences were found in plasma concentrations of insulin or of the counter-regulatory hormones between patients and control subjects. 6. It is concluded that the metabolic adaptation to short-term starvation in clinically stable human-immuno-deficiency-virus-infected patients differs from that in healthy control subjects. Short-term starvation results in a significantly greater fall in glucose turnover, whereas fat metabolism is clearly stimulated. These alterations cannot be explained by differences in the concentrations of insulin or of the counter-regulatory hormones.


Predictive and External Validity of a Pre-Market Study to Determine the Most Effective Pictorial Health Warning Label Content for Cigarette Packages.
Studies examining cigarette package pictorial health warning label (HWL) content have primarily used designs that do not allow determination of effectiveness after repeated, naturalistic exposure. This research aimed to determine the predictive and external validity of a pre-market evaluation study of pictorial HWLs. Data were analyzed from: (1) a pre-market convenience sample of 544 adult smokers who participated in field experiments in Mexico City before pictorial HWL implementation (September 2010); and (2) a post-market population-based representative sample of 1765 adult smokers in the Mexican administration of the International Tobacco Control Policy Evaluation Survey after pictorial HWL implementation. Participants in both samples rated six HWLs that appeared on cigarette packs, and also ranked HWLs with four different themes. Mixed effects models were estimated for each sample to assess ratings of relative effectiveness for the six HWLs, and to assess which HWL themes were ranked as the most effective. Pre- and post-market data showed similar relative ratings across the six HWLs, with the least and most effective HWLs consistently differentiated from other HWLs. Models predicting rankings of HWL themes in post-market sample indicated: (1) pictorial HWLs were ranked as more effective than text-only HWLs; (2) HWLs with both graphic and "lived experience" content outperformed symbolic content; and, (3) testimonial content significantly outperformed didactic content. Pre-market data showed a similar pattern of results, but with fewer statistically significant findings. The study suggests well-designed pre-market studies can have predictive and external validity, helping regulators select HWL content.


Variations in the hospital management of self-harm and patient outcome: a multi-site observational study in England.
Studies have shown wide variations in delivery of self-harm services but it is unclear how these relate to important outcomes such as self-harm repetition. Data were collected on self-harm presentations and hospital management from 31 hospitals in England. Key staff were interviewed about service provision for self-harm patients and responses were mapped to a 21-item service quality scale. Our main outcome was repeat hospital-presenting self-harm within six months. 6347 individuals presented with 7599 episodes of self-harm during a three month period in 2010-2011. Re-attendance with self-harm within six months of index episode occurred in 21% (1308/6347) of individuals (range between hospitals 9-27%). We found little association between clinical management at hospital level (i.e. proportion of episodes receiving psychosocial assessment, medical or psychiatric admission, and referral to statutory or non-statutory services) and repetition rate. The median score on service quality scale was 14.5 (range between hospitals 10.5-19). There was no evidence of correlation between total service quality score and repetition of self-harm (Spearman׳s r=-0.06, p=0.73) or between individual service items and repetition. We did not explore certain aspects of service provision e.g. quality of psychosocial assessments and length of admission. Hospital presentation for repeat self-harm may not be the most reliable measure of service quality. At aggregate level aspects of management and service structures did not appear to be associated with self-harm repetition rates. Future research should focus on better understanding the processes underlying the delivery of services at hospital level and their relationship to outcome.


Alberta physical activity and breast cancer prevention trial: sex hormone changes in a year-long exercise intervention among postmenopausal women.
We examined how an aerobic exercise intervention influenced circulating estradiol, estrone, sex hormone-binding globulin (SHBG), androstenedione, and testosterone levels, which may be involved in the association between physical activity and breast cancer risk. A two-center, two-arm randomized controlled trial of exercise was conducted in 320 postmenopausal, sedentary women age 50 to 74 years. Participants were randomly assigned to a 1-year aerobic exercise intervention of 225 min/wk (n = 160) or to a control group who maintained their usual level of activity (n = 160). Baseline, 6-month, and 12-month assessments of estrone, estradiol, androstenedione, and testosterone were quantified by radioimmunoassay after extraction, and SHBG was quantified by an immunometric assay. Intent-to-treat analyses were performed using linear mixed models. Blood data were available on 309 women (96.6%) at 12 months. Women in the intervention group exercised an average of 3.6 d/wk for 178 min/wk. At 12 months, statistically significant reductions in estradiol (treatment effect ratio [TER] = 0.93; 95% CI, 0.88 to 0.98) and free estradiol (TER = 0.91; 95% CI, 0.87 to 0.96) and increases in SHBG (TER = 1.04; 95% CI, 1.02 to 1.07) were observed in the exercise group compared with the control group. No significant differences in estrone, androstenedione, and testosterone levels were observed between exercisers and controls at 12 months. This trial found that previously sedentary postmenopausal women can adhere to a moderate- to vigorous-intensity exercise program that results in changes in estradiol and SHBG concentrations that are consistent with a lower risk for postmenopausal breast cancer.


[Pilot study of oral health policy and HIV].
To obtain and evaluate information on national oral health policies regarding patients with HIV/AIDS in the countries of the Americas. A cross-sectional descriptive study was conducted using an online questionnaire designed to be completed by the national oral health officials in the Region. Of the 38 countries that were asked to participate, only 12 (31.6%) completed the questionnaire. Of these 12, eight (66.7%) reported having national policies and strategies in place to promote oral health for the HIV/AIDS patient. Areas of study most explored by the countries over the last 5 years have been: (a) infection control practices; (b) the prevalence of HIV/AIDS-related oral lesions; (c) discrimination toward the HIV-positive patient during dental consultation; and, (d) dental coverage for infected individuals. Among the needs reported by the national officials of this sector were: increasing knowledge of good infection-control practices and HIV advances, development of forums for exchanging ideas and holding online discussions, and having access to information on sources of funding for studies and projects. Despite increased HIV/AIDS incidence and prevalence in the Americas, in general, there do not seem to be any model policies, strategies, or programs that address the issue of oral health and HIV infection. Establishing effective communication between dental health researchers and policymakers is imperative to confronting this epidemic, which increasingly requires more from the highly-trained dental professionals who offer quality of life to the affected population.


Radon 222 in drinking water resources of Iran: A systematic review, meta-analysis and probabilistic risk assessment (Monte Carlo simulation).
The current study was performed to review the conducted studies regarding the concentration of radon 222 in the tap drinking water; furthermore, by estimation of ingestion and inhalation effective dose, the health risk assessment in the adults and children using MCS technique was assessed. All related studies published among January 1990 to October 2016; were screened in the available databases such as Web of Science, PubMed, Science Direct, Scopus, SID, and Irandoc. The total effective dose was estimated by calculating Eing (Effective dose of ingestion) and Einh (Effective dose of inhalation) by Monte Carlo simulation (MCS) method. The range of ND ─ 40.9 Bq/L for radon 222 in water resources was proposed after evaluation of data collected from 13 studies with 1079 samples. The overall concentration of radon 222 in drinking water in Iran was 3.98: 95%CI (3.79 ─ 4.17 Bq/L). Also, the effective ingestion dose of radon 222 in adults age groups was 1.35 times higher than children. The rank order of drinking water resources based on the concentration of radon 222 was Spring > Spring and Well > Well > Spring and Qanat > Tap water. The overall concentration of radon 222 in drinking water in Iran was lower than WHO and EPA standard limits. Also, the rank order regarding area studied based on the concentration of radon 222 was Gillan > Mashhad > Mazandaran > Kerman > Yazd > Tehran > Kermanshah > Golestan > Hormozgan. The effective ingestion dose of radon 222 to consumers in the Gillan, Mashhad, Mazandaran, and Kerman were higher than WHO guidance (0.1 mSv/y). Also except consumers in the Hormozgan, inhalation effective dose radon 222, in the other investigated areas were higher than WHO guidance (0.1 mSv/y). Therefore, it is recommended to conduct the required programs regarding control and elimination of radon 222 concentration in Iranian drinking water supply.


Haemoglobin scavenging in intracranial bleeding: biology and clinical implications.
Haemoglobin is released into the CNS during the breakdown of red blood cells after intracranial bleeding. Extracellular free haemoglobin is directly neurotoxic. Haemoglobin scavenging mechanisms clear haemoglobin and reduce toxicity; these mechanisms include erythrophagocytosis, haptoglobin binding of haemoglobin, haemopexin binding of haem and haem oxygenase breakdown of haem. However, the capacity of these mechanisms is limited in the CNS, and they easily become overwhelmed. Targeting of haemoglobin toxicity and scavenging is, therefore, a rational therapeutic strategy. In this Review, we summarize the neurotoxic mechanisms of extracellular haemoglobin and the peculiarities of haemoglobin scavenging pathways in the brain. Evidence for a role of haemoglobin toxicity in neurological disorders is discussed, with a focus on subarachnoid haemorrhage and intracerebral haemorrhage, and emerging treatment strategies based on the molecular pathways involved are considered. By focusing on a fundamental biological commonality between diverse neurological conditions, we aim to encourage the application of knowledge of haemoglobin toxicity and scavenging across various conditions. We also hope that the principles highlighted will stimulate research to explore the potential of the pathways discussed. Finally, we present a consensus opinion on the research priorities that will help to bring about clinical benefits.


Post-surgical intestinal dysbiosis: use of an innovative mixture (Lactobacillus plantarum LP01, Lactobacillus lactis subspecies cremoris LLC02, Lactobacillus delbrueckii LDD01).
Abdominal surgery represents a high risk for hospital-acquired infections and complication that may compromise the surgery outcome. Patients with recent abdominal surgery have an intestinal dysbiosis. There is evidence that probiotics may counterbalance the impaired microbiota. Therefore, the current survey evaluated the efficacy and safety of Abincol®, an oral nutraceutical containing a probiotic mixture with Lactobacillus plantarum LP01 (1 billion of living cells), Lactobacillus lactis subspecies cremoris LLC02 (800 millions of living cells), and Lactobacillus delbrueckii LDD01 (200 millions of living cells), in 612 outpatients (344 males and 268 females, mean age 58 years) undergoing digestive surgery. Patients took 1 stick/daily for 8 weeks. Abincol® significantly diminished the presence and the severity of intestinal symptoms and improved stool form. In conclusion, the current survey suggests that Abincol® may be considered an effective and safe therapeutic option in the management of patients undergoing digestivesurgery.


Nanoscale dynamics of synaptic vesicle trafficking and fusion at the presynaptic active zone.
The cytomatrix at the active zone (CAZ) is a macromolecular complex that facilitates the supply of release-ready synaptic vesicles to support neurotransmitter release at synapses. To reveal the dynamics of this supply process in living synapses, we used super-resolution imaging to track single vesicles at voltage-clamped presynaptic terminals of retinal bipolar neurons, whose CAZ contains a specialized structure-the synaptic ribbon-that supports both fast, transient and slow, sustained modes of transmission. We find that the synaptic ribbon serves a dual function as a conduit for diffusion of synaptic vesicles and a platform for vesicles to fuse distal to the plasma membrane itself, via compound fusion. The combination of these functions allows the ribbon-type CAZ to achieve the continuous transmitter release required by synapses of neurons that carry tonic, graded visual signals in the retina.


Ovarian reserve screening: a scientific and ethical analysis.
Ovarian reserve (OR) screening of the general population is generally not advocated as it has not been conclusively established to reflect immediate potential for natural conception, while it may also potentially create anxiety for women. However, in this paper, we argue in support of screening of the general population for diminished OR. First, OR tests such as measurements of anti-Müllerian hormone and antral follicle count are predictive of the chances of IVF conception, and therefore predict a woman's total fertility potential (i.e. chances of natural and IVF-related conceptions). Since the requirement for assisted conception increases with age, this is an important point. Secondly, women identified as having low OR are at increased risk of early loss of fertility potential in the longer term, limiting their reproductive life span and the size of their family if they delay conception. Thirdly, women often disregard generic advice to avoid delaying conception beyond 30 years of age, yet studies suggest that personalized risk assessment tools such as OR testing can actually increase an individual's motivation for positive change. A poor OR screening test result is more likely to convince a woman to bring forward her plans for natural conception, or alternatively explore oocyte vitrification, at a stage when these approaches still have reasonable prospects of success. Finally, we believe that women have a right, based on the ethical concept of autonomy, to be made aware of OR screening, so that they themselves can determine if OR testing is useful in assisting them with reproductive life planning.


What do community football players think about different exercise-training programmes? Implications for the delivery of lower limb injury prevention programmes.
Players are the targeted end-users and beneficiaries of exercise-training programmes implemented during coach-led training sessions, and the success of programmes depends upon their active participation. Two variants of an exercise-training programme were incorporated into the regular training schedules of 40 community Australian Football teams, over two seasons. One variant replicated common training practices, while the second was an evidence-based programme to alter biomechanical and neuromuscular factors related to risk of knee injuries. This paper describes the structure of the implemented programmes and compares players' end-of-season views about the programme variants. This study was nested within a larger group-clustered randomised controlled trial of the effectiveness of two exercise-training programmes (control and neuromuscular control (NMC)) for preventing knee injuries. A post-season self-report survey, derived from Health Belief Model constructs, included questions to obtain players' views about the benefits and physical challenges of the programme in which they participated. Compared with control players, those who participated in the NMC programme found it to be less physically challenging but more enjoyable and potentially of more benefit. Suggestions from players about potential improvements to the training programme and its future implementation included reducing duration, increasing range of drills/exercises and promoting its injury prevention and other benefits to players. Players provide valuable feedback about the content and focus of implemented exercise-training programmes, that will directly inform the delivery of similar, or more successful, programmes in the future.


Resistance to RET-Inhibition in RET-Rearranged NSCLC Is Mediated By Reactivation of RAS/MAPK Signaling.
Oncogenic rearrangements in RET are present in 1%-2% of lung adenocarcinoma patients. Ponatinib is a multi-kinase inhibitor with low-nanomolar potency against the RET kinase domain. Here, we demonstrate that ponatinib exhibits potent antiproliferative activity in RET fusion-positive LC-2/ad lung adenocarcinoma cells and inhibits phosphorylation of the RET fusion protein and signaling through ERK1/2 and AKT. Using distinct dose escalation strategies, two ponatinib-resistant LC-2/ad cell lines, PR1 and PR2, were derived. PR1 and PR2 cell lines retained expression, but not phosphorylation of the RET fusion and lacked evidence of a resistance mutation in the RET kinase domain. Both resistant lines retained activation of the MAPK pathway. Next-generation RNA sequencing revealed an oncogenic NRAS p.Q61K mutation in the PR1 cell. PR1 cell proliferation was preferentially sensitive to siRNA knockdown of NRAS compared with knockdown of RET, more sensitive to MEK inhibition than the parental line, and NRAS dependence was maintained in the absence of chronic RET inhibition. Expression of NRAS p.Q61K in RET fusion expressing TPC1 cells conferred resistance to ponatinib. PR2 cells exhibited increased expression of EGFR and AXL. EGFR inhibition decreased cell proliferation and phosphorylation of ERK1/2 and AKT in PR2 cells, but not LC-2/ad cells. Although AXL inhibition enhanced PR2 sensitivity to afatinib, it was unable to decrease cell proliferation by itself. Thus, EGFR and AXL cooperatively rescued signaling from RET inhibition in the PR2 cells. Collectively, these findings demonstrate that resistance to ponatinib in RET-rearranged lung adenocarcinoma is mediated by bypass signaling mechanisms that result in restored RAS/MAPK activation. Mol Cancer Ther; 16(8); 1623-33. ©2017 AACR.


The Happiest Kids on Earth. Gender Equality and Adolescent Life Satisfaction in Europe and North America.
Cross-national differences in adolescent life satisfaction in Europe and North America are consistent, but remain poorly understood. While previous studies have predominantly focused on the explanatory role of economic factors, such as national wealth and income equality, they revealed weak associations, at most. This study examines whether societal gender equality can explain the observed cross-national variability in adolescent life satisfaction. Based on the assumption that gender equality fosters a supportive social context, for example within families through a more equal involvement of fathers and mothers in child care tasks, adolescent life satisfaction was expected to be higher in more gender-equal countries. To test this hypothesis, national-level data of gender equality (i.e., women's share in political participation, decision making power, economic participation and command over resources) were linked to data from 175,470 adolescents aged 11-16 years old (M age = 13.6, SD = 1.64, 52% girls) from 34 European and North American countries involved in the 2009/10 Health Behaviour in School-aged Children (HBSC) study. Results of linear multilevel regression analyses indicate that adolescents in countries with relatively high levels of gender equality report higher life satisfaction than their peers in countries with lower levels of gender equality. The association between gender equality and adolescent life satisfaction remained significant after controlling for national wealth and income equality. It was equally strong for boys and girls. Moreover, the association between gender equality and life satisfaction was explained by social support in the family, peer and school context. This analysis suggests that gender equality fosters social support among members of a society, which in turn contributes to adolescent life satisfaction. Thus, promoting gender equality is likely to benefit all members of a society; not just by giving equal rights to women and girls, but also by fostering a supportive social climate for all.


Ageing and reproduction: antioxidant supplementation alleviates telomere loss in wild birds.
Reproduction is inherently costly. Environmental stressors, such as infection and limited food resources, can compromise investment at each breeding attempt. For example, recent data on captive birds showed that increased reproductive effort accelerates ageing. However, the effects of nutritional status and infection on ageing remain unknown. Telomeres function as protective caps at the ends of eukaryotic chromosomes, and changes in telomere length is a commonly used proxy for ageing. To partially address the mechanisms of ageing following reproduction, we supplemented, medicated or administered a combined treatment to wild blue tits (Cyanistes caeruleus) breeding in central Spain during 2012. The nutritional supplement consisted of two different antioxidants, whereas the medication was an antimalarial treatment against blood parasites. We evaluated the effect of these manipulations on reproductive success and parasite loads in the first breeding season, and on changes in telomere length between two consecutive breeding seasons. Supplemented birds showed no reduction in blood parasite infections in 2012, although they exhibited higher body mass and fledging success. The antimalarial drugs reduced infections by several parasite species, but this had no effect on fitness parameters. In the following season, telomeres from supplemented birds had shortened less. Altogether, we found that supplementation with antioxidants provided fitness benefits in the short term and reduced telomere loss a year following treatment. Our results provide indirect empirical support for accelerated telomere loss as a cost of reproduction.


HO-1 overexpression and underexpression: Clinical implications.
In this review we examine the effects of both over- and under-production of heme oxygenase-1 (HO-1) and HO activity on a broad spectrum of biological systems and on vascular disease. In a few instances e.g., neonatal jaundice, overproduction of HO-1 and increased HO activity results in elevated levels of bilirubin requiring clinical intervention with inhibitors of HO activity. In contrast HO-1 levels and HO activity are low in obesity and the HO system responds to mitigate the deleterious effects of oxidative stress through increased levels of bilirubin (anti-inflammatory) and CO (anti-apoptotic) and decreased levels of heme (pro-oxidant). Site specific HO-1 overexpression diminishes adipocyte terminal differentiation and lipid accumulation of obesity mediated release of inflammatory molecules. A series of diverse strategies have been implemented that focus on increasing HO-1 and HO activity that are central to reversing the clinical complications associated with diseases including, obesity, metabolic syndrome and vascular disease.


Analysis of secreted proteins using SILAC.
Secreted proteins serve a crucial role in the communication between cells, tissues, and organs. Proteins released to the extracellular environment exert their function either locally or at distant points of the organism. Proteins are secreted in a highly dynamic fashion by cells and tissues in the body responding to the stimuli and requirements presented by the extracellular milieu. Characterization of secretomes derived from various cell types has been performed using different quantitative mass spectrometry-based proteomics strategies, several of them taking advantage of labeling with stable isotopes. Here, we describe the use of Stable Isotope Labeling by Amino acids in Cell culture (SILAC) for the quantitative analysis of the skeletal muscle secretome during myogenesis.


Safety and immunological responses to human mesenchymal stem cell therapy in difficult-to-treat HIV-1-infected patients.
HAART largely decreases morbidity and mortality in chronic HIV-1-infected patients, but immune nonresponders (INRs) with full viral suppression still fail to reverse the immune deficiency. This study evaluated the safety and immunological responses of human umbilical cord mesenchymal stem cell (MSC) therapy in HIV-1-infected INRs. A total of 13 HIV-1-infected INRs were enrolled in this pilot prospectively open-labeled controlled clinical trial. Seven patients were administered three umbilical cord-MSC transfusions at 1-month interval during 12-months of follow-up, whereas six control patients were treated with saline in parallel. Immunological parameters were monitored in these patients throughout the trial. All patients tolerated the umbilical cord-MSC transfusions well throughout the trial. The umbilical cord-MSC transfusions preferentially increased circulating naive and central memory CD4 T-cell counts and restored HIV-1-specific IFN-γ and IL-2 production in the INRs. These enhancements in immune reconstitution were also associated with the reduction of systemic immune activation and inflammation in vivo. umbilical cord-MSC transfusions are well tolerated and can efficiently improve host immune reconstitution in INRs, suggesting that such treatments may be used as a novel immunotherapeutic approach to reversing immune deficiency in HIV-1-infected INRs (ClinicalTrials.gov identifier: NCT01213186).


Biohydrogenation of dietary n-3 PUFA and stability of ingested vitamin E in the rumen, and their effects on microbial activity in sheep.
The present study investigated the susceptibility of dietary n-3 PUFA to ruminal biohydrogenation, the stability of ingested vitamin E in the rumen and the subsequent uptake of PUFA and vitamin E into plasma. Six cannulated sheep were assigned to six diets over five 33 d periods, in an incomplete 6x5 Latin square. The diets, based on dried grass, were formulated to supply 50 g fatty acids/kg DM using three lipid sources: Megalac (calcium soap of palm fatty acid distillate; Volac Ltd, Royston, Herts., UK), linseed (formaldehyde-treated; Trouw Nutrition, Northwich, Ches., UK) and linseed-fish oil (formaldehyde-treated linseed+fish oil). The diets were supplemented with 100 or 500 mg alpha-tocopheryl acetate/kg DM. Fat source or level of vitamin E in the diet did not alter microbial activity in the rumen. Biohydrogenation of linoleic acid (18 : 3n-6; 85-90 %), linolenic acid (18 : 3n-3; 88-93 %), docosahexaenoic acid (22 : 6n-3; 91 %) and EPA (20 : 5n-3; 92 %) was extensive. Feeding formaldehyde-treated linseed elevated concentrations of 18 : 3n-3 in plasma, whilst 22 : 6n-3 and 20 : 5n-3 were only increased by feeding the linseed-fish oil blend. Duodenal recovery of ingested vitamin E was high (range 0.79-0.92 mg/mg fed). High dietary vitamin E was associated with increased plasma alpha-tocopherol (2.57 v. 1.46 microg/ml for 500 and 100 mg alpha-tocopheryl acetate/kg DM respectively), although all concentrations were low. Plasma vitamin E levels, however, tended to decrease as the type and quantity of PUFA in the diet increased. The present study illustrates that nutritionally beneficial PUFA in both fish and linseed oils are highly susceptible to biohydrogenation in the rumen. Although alpha-tocopheryl acetate resisted degradation in the rumen, plasma vitamin E status remained deficient to borderline, suggesting either that uptake may have been impaired or metabolism post-absorption increased.


Log-Transformed Electromyography Amplitude-Power Output Relationship: Single-Leg Knee-Extensor Versus Single-Leg Cycle Ergometry.
Noble, EB, Pilarski, JM, Vora, HK, Zuniga, JM, and Malek, MH. Log-transformed electromyography amplitude-power output relationship: single-leg knee-extensor versus single-leg cycle ergometry. J Strength Cond Res 33(5): 1311-1319, 2019-Comparing and contrasting motor unit recruitment and activation for the same muscles for multiple versus single-joint exercise may provide a better understanding of neuromuscular fatigue. The purpose of this study, therefore, is to compare the slope and y-intercept terms for the 3 superficial quadriceps femoris (QF) (vastus lateralis, rectus femoris, and vastus medialis) muscles derived from the log-transformed electromyography (EMG) amplitude-power output relationship between the single-leg knee-extensor ergometry (KE) and the single-leg cycle ergometry (CE). Ten healthy college-aged men who engaged in regular physical activity visited the laboratory on 2 occasions separated by 7 days to perform either single-leg CE or single-leg KE in a randomized order. For each visit, subjects performed incremental exercise until voluntary fatigue. Electromyography electrodes were placed on the superficial QF muscles. The slope and y-intercept terms, for each muscle, for the EMG amplitude versus power output relationship was examined using the log-transformed model for each subject's data. The results indicated no significant (p > 0.05) mean differences for either slope or y-intercept terms between exercise modes and across muscles. In addition, separate repeated-measures analyses of variance (ANOVAs) were used to determine mean differences for the slope and y-intercept values between the 3 muscles. In addition, separate 2 (mode: CE or KE) × intensity (intensity: 30, 60, and 90% of maximal workload) repeated-measures ANOVAs were conducted for each muscle. There was a significant (p < 0.05) mode × exercise intensity interaction for each muscle. Follow-up testing indicated that in most cases, the normalized EMG amplitude was significantly higher for single-leg KE than single-leg CE. These results indicated that incremental single-leg KE activates the superficial QF muscles significantly greater than single-leg CE.


Silybin supplementation during HCV therapy with pegylated interferon-α plus ribavirin reduces depression and anxiety and increases work ability.
Hepatitis C virus infection and interferon treatment are often associated with anxiety, depressive symptoms and poor health-related quality of life. To evaluate the Silybin-vitamin E-phospholipids complex effect on work ability and whether health related factors (anxiety and depression) were associated with work ability in subjects with chronic hepatitis C treated with Pegylated-Interferon-α2b (Peg-IFN) and Ribavirin (RBV). Thirty-one patients (Group A) with chronic hepatitis and other 31 subjects in Group B were recruited in a randomized, prospective, placebo controlled, double blind clinical trial. Group A received 1.5 mg/kg per week of Peg-IFN plus RBV and placebo, while Group B received the same dosage of Peg-IFN plus RBV plus association of Silybin 94 mg + vitamin E 30 mg + phospholipids 194 mg in pills for 12 months. All subjects underwent to laboratory exams and questionnaires to evaluate depression (Beck Depression Inventory - BDI), anxiety (State-trait anxiety inventory - STAI) and work ability (Work ability Index - WAI). The comparison between group A and group B showed significant differences after 6 months in ALT (P < 0.001), and viremia (P < 0.05), after 12 months in ALT (P < 0.001), and AST (P < 0.001), at follow up in AST (P < 0.05), and ALT (P < 0.001). Significant difference were observed after 1 month in WAI (p < 0.001) and BDI (P < 0.05), after 6 months in WAI (P < 0.05) and STAI (P < 0.05), after 12 months and at follow up in WAI, STAI and BDI (p < 0.01). The supplementation with Silybin-vitamin E -phospholipids complex increased work ability and reduced depression and anxiety in patients treated with Peg-IFN and RBV. NCT01957319 , First received: September 25, 2013. Last updated: September 30, 2013 (retrospectively registered).


De novo genome assembly and annotation of Australia's largest freshwater fish, the Murray cod (Maccullochella peelii), from Illumina and Nanopore sequencing read.
One of the most iconic Australian fish is the Murray cod, Maccullochella peelii (Mitchell 1838), a freshwater species that can grow to ∼1.8 metres in length and live to age ≥48 years. The Murray cod is of a conservation concern as a result of strong population contractions, but it is also popular for recreational fishing and is of growing aquaculture interest. In this study, we report the whole genome sequence of the Murray cod to support ongoing population genetics, conservation, and management research, as well as to better understand the evolutionary ecology and history of the species. A draft Murray cod genome of 633 Mbp (N50 = 109 974bp; BUSCO and CEGMA completeness of 94.2% and 91.9%, respectively) with an estimated 148 Mbp of putative repetitive sequences was assembled from the combined sequencing data of 2 fish individuals with an identical maternal lineage; 47.2 Gb of Illumina HiSeq data and 804 Mb of Nanopore data were generated from the first individual while 23.2 Gb of Illumina MiSeq data were generated from the second individual. The inclusion of Nanopore reads for scaffolding followed by subsequent gap-closing using Illumina data led to a 29% reduction in the number of scaffolds and a 55% and 54% increase in the scaffold and contig N50, respectively. We also report the first transcriptome of Murray cod that was subsequently used to annotate the Murray cod genome, leading to the identification of 26 539 protein-coding genes. We present the whole genome of the Murray cod and anticipate this will be a catalyst for a range of genetic, genomic, and phylogenetic studies of the Murray cod and more generally other fish species of the Percichthydae family.


Pure phase modulation based on a silicon plasma dispersion modulator.
Plasma dispersion modulators (PDMs), such as carrier injection modulators and carrier depletion modulators, are widely used for high speed phase modulation in silicon photonic circuits, but they suffer from spurious intensity modulation. This can be a problem in coherent communication systems that make use of complex multi-level quadrature modulation formats, as well as analog applications such as microwave photonics. In this article, a method to achieve pure phase modulation using PDMs is proposed based on a configurable modulator circuit. The configurable modulator is implemented as a Mach-Zehnder interferometer with a PDM and tunable couplers (TCs). The spurious intensity modulation of the phase modulated lightwave can be compensated by tuning the coupling ratios of the TCs and the phase delay between the two arms of the MZI. Simulation results show that for a depletion modulator, the 1.26 dB spurious intensity modulation can be suppressed down to 0.023 dB within a phase range of 0.4π, and for injection modulator, the 1.27 dB spurious intensity modulation can be suppressed down to 0.07 dB within a phase range of 0.76π.


In search of fewer independent risk factors.
More than 1100 articles now appear annually investigating "independent risk factors" or "independent predictors" for various clinical outcomes. In medical research, independence is generally defined in a statistical sense: a variable is called an independent risk factor if it has a significant contribution to an outcome in a statistical model that includes established risk factors. As such, independence is based on a specific statistical model and depends on the set of established risk factors included in that model. Even when strong statistical evidence indicates that a variable is an independent risk factor for an outcome, this does not necessarily indicate that the risk factor causally contributes to the outcome. The opposite is also true: risk factors that have causal relationships with the outcome will not necessarily prove to be independent risk factors. These are basic statistical principles that are too often given short shrift in medical research. Herein, we discuss the clinical implications conferred by the above definition of independence, primarily using examples from recent cardiovascular literature. A glossary and schema are provided to help clinicians and researchers understand and discuss these matters effectively.


A fast and precise indoor localization algorithm based on an online sequential extreme learning machine.
Nowadays, developing indoor positioning systems (IPSs) has become an attractive research topic due to the increasing demands on location-based service (LBS) in indoor environments. WiFi technology has been studied and explored to provide indoor positioning service for years in view of the wide deployment and availability of existing WiFi infrastructures in indoor environments. A large body of WiFi-based IPSs adopt fingerprinting approaches for localization. However, these IPSs suffer from two major problems: the intensive costs of manpower and time for offline site survey and the inflexibility to environmental dynamics. In this paper, we propose an indoor localization algorithm based on an online sequential extreme learning machine (OS-ELM) to address the above problems accordingly. The fast learning speed of OS-ELM can reduce the time and manpower costs for the offline site survey. Meanwhile, its online sequential learning ability enables the proposed localization algorithm to adapt in a timely manner to environmental dynamics. Experiments under specific environmental changes, such as variations of occupancy distribution and events of opening or closing of doors, are conducted to evaluate the performance of OS-ELM. The simulation and experimental results show that the proposed localization algorithm can provide higher localization accuracy than traditional approaches, due to its fast adaptation to various environmental dynamics.