'Faking til you make it': social capital accumulation of individuals on low incomes living in contrasting socio-economic neighbourhoods and its implications for health and wellbeing.
People on low-income living in low socio-economic neighbourhoods have poorer health in comparison with those living in advantaged neighbourhoods. To explore neighbourhood effects on health and social capital creation, the experiences of low-income people living in contrasting socio-economic neighbourhoods were compared, in order to examine how low-income status and differing levels of neighbourhood resources contributed to perceived health and wellbeing. Quantitative and qualitative data were analysed: survey data from 601 individuals living in contrasting socio-economic areas and in-depth interviews with a new sample of 24 individuals on low-incomes. The study was guided by Bourdieu's theory of practice, which examines how social inequalities are created and reproduced through the relationship between individuals' varying resources of economic, social and cultural capital. This included an examination of individual life histories, cultural distinction and how social positions are reproduced. Participants' accounts of their early life experience showed how parental socio-economic position and socially patterned events taking place across the life course, created different opportunities for social network creation, choice of neighbourhood and levels of resources available throughout life, all of which can influence health and wellbeing. A definition of poverty by whether an individual or household has sufficient income at a particular point in time was an inadequate measure of disadvantage. This static measure of 'low income' as a category disguised a number of different ways in which disadvantage was experienced or, conversely, how life course events could mitigate the impact of low-income. This study found that the resources necessary to create social capital such as cultural capital and the ability to socially network, differed according to the socio-economic status of the neighbourhood, and that living in an advantaged area does not automatically guarantee access to potentially beneficial social networks.


Functional recovery measures for spinal cord injury: an evidence-based review for clinical practice and research.
The end goal of clinical care and clinical research involving spinal cord injury (SCI) is to improve the overall ability of persons living with SCI to function on a daily basis. Neurologic recovery does not always translate into functional recovery. Thus, sensitive outcome measures designed to assess functional status relevant to SCI are important to develop. Evaluation of currently available SCI functional outcome measures by a multinational work group. The 4 measures that fit the prespecified inclusion criteria were the Modified Barthel Index (MBI), the Functional Independence Measure (FIM), the Quadriplegia Index of Function (QIF), and the Spinal Cord Independence Measure (SCIM). The MBI and the QIF were found to have minimal evidence for validity, whereas the FIM and the SCIM were found to be reliable and valid. The MBI has little clinical utility for use in the SCI population. Likewise, the FIM applies mainly when measuring burden of care, which is not necessarily a reflection of functional recovery. The QIF is useful for measuring functional recovery but only in a subpopulation of people with SCI, and substantial validity data are still required. The SCIM is the only functional recovery outcome measure designed specifically for SCI. The multinational work group recommends that the latest version of the SCIM (SCIM III) continue to be refined and validated and subsequently implemented worldwide as the primary functional recovery outcome measure for SCI. The QIF may continue to be developed and validated for use as a supplemental tool for the nonambulatory tetraplegic population.


Methicillin-resistant Staphylococcus aureus strain USA300: origin and epidemiology.
Methicillin-resistant Staphylococcus aureus (MRSA) PFGE strain type USA300 (multilocus sequence type 8, clonal complex 8, staphylococcal cassette chromosome mec type IV) was first reported in the USA as a cause of skin and soft issue infection among college football players in Pennsylvania and among prisoners in Missouri in 2000. Over the next 5 years, USA300 became the predominant community-associated MRSA strain in the USA. It was the most common PFGE type recovered from skin and soft tissue infections in persons presenting to 11 emergency departments across the USA, and caused outbreaks in Native American populations, children in daycare centres, military recruits, prison inmates and among men who have sex with men. Although predominantly a cause of skin and soft issue infection, USA300 isolates also have been recovered from cases of invasive disease including bacteraemia, endocarditis, severe necrotizing pneumonia and osteomyelitis. Isolates of USA300 usually carry the genes encoding the Panton-Valentine leucocidin and the arginine catabolic mobile element, but rarely carry staphylococcal enterotoxin genes. USA300 isolates are becoming more resistant to antimicrobial agents, including erythromycin, levofloxacin, mupirocin and tetracycline, and have spread to Europe, South America and Australia. The emergence of the MRSA USA300 strain type represents a unique biological success story.


Integrated collaborative care for major depression comorbid with a poor prognosis cancer (SMaRT Oncology-3): a multicentre randomised controlled trial in patients with lung cancer.
The management of depression in patients with poor prognosis cancers, such as lung cancer, creates specific challenges. We aimed to assess the efficacy of an integrated treatment programme for major depression in patients with lung cancer compared with usual care. Symptom Management Research Trials (SMaRT) Oncology-3 is a parallel-group, multicentre, randomised controlled trial. We enrolled patients with lung cancer and major depression from three cancer centres and their associated clinics in Scotland, UK. Participants were randomly assigned in a 1:1 ratio to the depression care for people with lung cancer treatment programme or usual care by a database software algorithm that used stratification (by trial centre) and minimisation (by age, sex, and cancer type) with allocation concealment. Depression care for people with lung cancer is a manualised, multicomponent collaborative care treatment that is systematically delivered by a team of cancer nurses and psychiatrists in collaboration with primary care physicians. Usual care is provided by primary care physicians. The primary outcome was depression severity (on the Symptom Checklist Depression Scale [SCL-20], range 0-4) averaged over the patient's time in the trial (up to a maximum of 32 weeks). Trial statisticians and data collection staff were masked to treatment allocation, but patients and clinicians could not be masked to the allocations. Analyses were by intention to treat. This trial is registered with Current Controlled Trials, number ISRCTN75905964. 142 participants were recruited between Jan 5, 2009, and Sept 9, 2011; 68 were randomly allocated to depression care for people with lung cancer and 74 to usual care. 43 (30%) of 142 patients had died by 32 weeks, all of which were cancer-related deaths. No intervention-related serious adverse events occurred. 131 (92%) of 142 patients provided outcome data (59 in the depression care for people with lung cancer group and 72 in the usual care group) and were included in the intention-to-treat primary analysis. Average depression severity was significantly lower in patients allocated to depression care for people with lung cancer (mean score on the SCL-20 1·24 [SD 0·64]) than in those allocated to usual care (mean score 1·61 [SD 0·58]); difference -0·38 (95% CI -0·58 to -0·18); standardised mean difference -0·62 (95% CI -0·94 to -0·29). Self-rated depression improvement, anxiety, quality of life, role functioning, perceived quality of care, and proportion of patients achieving a 12-week treatment response were also significantly better in the depression care for people with lung cancer group than in the usual care group. Our findings suggest that major depression can be treated effectively in patients with a poor prognosis cancer; integrated depression care for people with lung cancer was substantially more efficacious than was usual care. Larger trials are now needed to estimate the effectiveness and cost-effectiveness of this care programme in this patient population, and further adaptation of the treatment will be necessary to address the unmet needs of patients with major depression and even shorter life expectancy. Cancer Research UK and Chief Scientist Office of the Scottish Government.


Negative Gaussian curvature induces significant suppression of thermal conduction in carbon crystals.
From the mathematic category of surface Gaussian curvature, carbon allotropes can be classified into three types: zero curvature, positive curvature, and negative curvature. By performing Green-Kubo equilibrium molecular dynamics simulations, we found that surface curvature has a significant impact on the phonon vibration and thermal conductivity (κ) of carbon crystals. When curving from zero curvature to negative or positive curvature structures, κ is reduced by several orders of magnitude. Interestingly, we found that κ of negatively curved carbon crystals exhibits a monotonic dependence on curvature. Through phonon mode analysis, we show that curvature induces remarkable phonon softening in phonon dispersion, which results in the reduction of phonon group velocity and flattening of phonon band structure. Furthermore, the curvature was found to induce phonon mode hybridization, leading to the suppression of phonon relaxation time. Our study provides physical insight into thermal transport in curvature materials, and will be valuable in the modulation of phonon activity through surface curvature.


Age-related factors in cyclosporine-induced syngeneic graft-versus-host disease: regulatory role of marrow-derived T lymphocytes.
The present studies have evaluated the effect of age on the induction of syngeneic graft-versus-host disease (SGVHD) after syngeneic bone marrow transplantation (BMT) and cyclosporine (CsA) therapy. The results clearly document an inverse correlation of age with the incidence of SGVHD. Virtually a 100% incidence of SGVHD occurs in Lewis rats when syngeneic BMT and CsA therapy are started when the animals are 4 wk of age. Thereafter, there is a dramatic decline in the incidence of SGVHD with the increasing age of the animals. Although the age of the recipient was important, the most significant effect was the age of the marrow donor. Marrow from animals 6 mo of age was virtually incapable of eliciting SGVHD after BMT and CsA therapy. Furthermore, mixing the marrow from mature and immature animals resulted in a decreased incidence of SGVHD, implicating a regulatory effect present in the marrow from older rats. This regulatory effect was due to the presence of mature T cells in the marrow from animals 6 mo of age. Despite the fact that marrow from young animals possesses mature T lymphocytes, this regulatory activity was absent, suggesting that the host resistance mediated by T lymphocytes develops as the animal ages. These data further implicate the importance of a host resistance mechanism in preventing the induction of SGVHD with CsA, which appears to be mediated by the clonal inactivation of autoreactive cells.


Development of microRNA-21 mimic nanocarriers for the treatment of cutaneous wounds.
Rationale: Of the regulatory microRNAs expressed in the wounded skin, microRNA-21 (miR21) plays a pivotal role in wound repair by stimulating re-epithelialization, an essential feature to facilitate healing and reduce scar formation. Despite their crucial roles in wound healing, synthetic exogenous microRNAs have limited applications owing to the lack of an appropriate delivery system. Herein, we designed an miR21 mimic nanocarrier system using facial amphipathic bile acid-conjugated polyethyleneimines (BA-PEI) for the intracellular and transdermal delivery of synthetic miR21 molecules to accelerate wound repair. Methods: To design miR21 mimic nanocarriers, BA-conjugated PEIs prepared from three different types of BA at molar feed ratios of 1 and 3 were synthesized. The intracellular uptake efficiency of synthetic miR21 mimics was studied using confocal laser scanning microscopy and flow cytometry analysis. The optimized miR21/BA nanocarrier system was used to evaluate the wound healing effects induced by miR21 mimics in human HaCaT keratinocytes in vitro and a murine excisional acute wound model in vivo. Results: The cell uptake efficiency of miR21 complexed with BA-conjugated PEI was dramatically higher than that of miR21 complexed with PEI alone. Deoxycholic acid (DA)-modified PEI at a molar feed ratio of 3:1 (DA3-PEI) showed the highest transfection efficiency for miR21 without any increase in toxicity. After effective transdermal and intracellular delivery of miR21/DA3 nanocarriers, miR21 mimics promoted cell migration and proliferation through the post-transcriptional regulation of programmed cell death protein 4 (PDCD4) and matrix metalloproteinases. Thus, miR21 mimic nanocarriers improved both the rate and quality of wound healing, as evident from enhanced collagen synthesis and accelerated wound re-epithelialization. Conclusion: Our miRNA nanocarrier systems developed using DA3-PEI conjugates may be potentially useful for the delivery of synthetic exogenous miRNAs in various fields.


A survey of locus-specific database curation. Human Genome Variation Society.
It is widely accepted that curation of variation in genes is best performed by experts in those genes and their variation. However, obtaining funding for such variation is difficult even though up-to-date lists of variations in genes are essential for optimum delivery of genetic healthcare and for medical research. This study was undertaken to gather information on gene-specific databases (locus-specific databases) in an effort to understand their functioning, funding and needs. A questionnaire was sent to 125 curators and we received 47 responses. Individuals performed curation of up to 69 genes. The time curators spent curating was extremely variable. This ranged from 0 h per week up to 5 curators spending over 4 h per week. The funding required ranged from US$600 to US$45,000 per year. Most databases were stimulated by the Human Genome Organization-Mutation Database Initiative and used their guidelines. Many databases reported unpublished mutations, with all but one respondent reporting errors in the literature. Of the 13 who reported hit rates, 9 reported over 52,000 hits per year. On the basis of this, five recommendations were made to improve the curation of variation information, particularly that of mutations causing single-gene disorder: 1. A curator for each gene, who is an expert in it, should be identified or nominated. 2. Curation at a minimum of 2 h per week at US$2000 per gene per year should be encouraged. 3. Guidelines and custom software use should be encouraged to facilitate easy setup and curation. 4. Hits per week on the website should be recorded to allow the importance of the site to be illustrated for grant-giving purposes. 5. Published protocols should be followed in the establishment of locus-specific databases.


Safety Recommendations for Evaluation and Surgery of the Head and Neck During the COVID-19 Pandemic.
The rapidly expanding novel coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2, has challenged the medical community to an unprecedented degree. Physicians and health care workers are at added risk of exposure and infection during the course of patient care. Because of the rapid spread of this disease through respiratory droplets, health care workers who come in close contact with the upper aerodigestive tract during diagnostic and therapeutic procedures, such as otolaryngologists-head and neck surgeons, are particularly at risk. A set of safety recommendations was created based on a review of the literature and communications with physicians with firsthand knowledge of safety procedures during the COVID-19 pandemic. A high number of health care workers were infected during the first phase of the pandemic in the city of Wuhan, China. Subsequently, by adopting strict safety precautions, other regions were able to achieve high levels of safety for health care workers without jeopardizing the care of patients. The most common procedures related to the examination and treatment of upper aerodigestive tract diseases were reviewed. Each category was reviewed based on the potential risk imposed to health care workers. Specific recommendations were made based on the literature, when available, or consensus best practices. Specific safety recommendations were made for performing tracheostomy in patients with COVID-19. Preserving a highly skilled health care workforce is a top priority for any community and health care system. Based on the experience of health care systems in Asia and Europe, by following strict safety guidelines, the risk of exposure and infection of health care workers could be greatly reduced while providing high levels of care. The provided recommendations, which may evolve over time, could be used as broad guidance for all health care workers who are involved in the care of patients with COVID-19.


IgG Donor-Specific Anti-Human HLA Antibody Subclasses and Kidney Allograft Antibody-Mediated Injury.
Antibodies may have different pathogenicities according to IgG subclass. We investigated the association between IgG subclasses of circulating anti-human HLA antibodies and antibody-mediated kidney allograft injury. Among 635 consecutive kidney transplantations performed between 2008 and 2010, we enrolled 125 patients with donor-specific anti-human HLA antibodies (DSA) detected in the first year post-transplant. We assessed DSA characteristics, including specificity, HLA class specificity, mean fluorescence intensity (MFI), C1q-binding, and IgG subclass, and graft injury phenotype at the time of sera evaluation. Overall, 51 (40.8%) patients had acute antibody-mediated rejection (aABMR), 36 (28.8%) patients had subclinical ABMR (sABMR), and 38 (30.4%) patients were ABMR-free. The MFI of the immunodominant DSA (iDSA, the DSA with the highest MFI level) was 6724±464, and 41.6% of patients had iDSA showing C1q positivity. The distribution of iDSA IgG1-4 subclasses among the population was 75.2%, 44.0%, 28.0%, and 26.4%, respectively. An unsupervised principal component analysis integrating iDSA IgG subclasses revealed aABMR was mainly driven by IgG3 iDSA, whereas sABMR was driven by IgG4 iDSA. IgG3 iDSA was associated with a shorter time to rejection (P<0.001), increased microcirculation injury (P=0.002), and C4d capillary deposition (P<0.001). IgG4 iDSA was associated with later allograft injury with increased allograft glomerulopathy and interstitial fibrosis/tubular atrophy lesions (P<0.001 for all comparisons). Integrating iDSA HLA class specificity, MFI level, C1q-binding status, and IgG subclasses in a Cox survival model revealed IgG3 iDSA and C1q-binding iDSA were strongly and independently associated with allograft failure. These results suggest IgG iDSA subclasses identify distinct phenotypes of kidney allograft antibody-mediated injury.


Dark matter detectors as dark photon helioscopes.
Light new particles with masses below 10 keV, often considered as a plausible extension of the standard model, will be emitted from the solar interior and can be detected on Earth with a variety of experimental tools. Here, we analyze the new "dark" vector state V, a massive vector boson mixed with the photon via an angle κ, that in the limit of the small mass mV has its emission spectrum strongly peaked at low energies. Thus, we utilize the constraints on the atomic ionization rate imposed by the results of the XENON10 experiment to set the limit on the parameters of this model: κ×mV<3×10(-12) eV. This makes low-threshold dark matter experiments the most sensitive dark vector helioscopes, as our result not only improves current experimental bounds from other searches by several orders of magnitude but also surpasses even the most stringent astrophysical and cosmological limits in a seven-decade-wide interval of mV. We generalize this approach to other light exotic particles and set the most stringent direct constraints on "minicharged" particles.


Creating second-order nonlinearity in pure synthetic silica optical fibers by thermal poling.
A twin-hole optical fiber with pure synthetic silicate glass between the two electrode holes was thermally poled. The induced second-order nonlinearity (SON) was located at the core-cladding interface sections that were nearly parallel to the poling electric field. The polarization dependence of the induced SON suggests that nonlinearity was due to the presence of a space-charge field, which was probably formed by electron migration among the defects located at the core-cladding interface. The magnitude of the induced SON was measured to be approximately 0.06 pm /V.


Self-reported hepatitis C virus antibody status and risk behavior in young injectors.
This study was conducted to assess the accuracy of self-reported hepatitis C virus (HCV) antibody (anti-HCV) serostatus in injection drug users (IDUs), and examine whether self-reported anti-HCV serostatus was associated with recent injection risk behavior. In five U.S. cities (Baltimore, Chicago, Los Angeles, New York, and Seattle), 3,004 IDUs from 15 to 30 years old were recruited for a baseline interview to determine eligibility for a randomized controlled trial of a behavioral intervention. HIV and HCV antibody testing were performed, and subject data (e.g., demographics, drug and sexual risk behavior, and history of HIV and HCV testing) were collected via audio computer-administered self-interview. Risk behavior during the previous three months was compared to self-reported anti-HCV serostatus. Anti-HCV prevalence in this sample of young IDUs was 34.1%. Seventy-two percent of anti-HCV-positive and 46% of anti-HCV-negative IDUs in this sample were not aware of their HCV serostatus. Drug treatment or needle exchange use was associated with increased awareness of HCV serostatus. Anti-HCV-negative IDUs who knew their serostatus were less likely than those unaware of their status to inject with a syringe used by another IDU or to share cottons to filter drug solutions. Knowledge of one's positive anti-HCV status was not associated with safer injection practices. Few anti-HCV-positive IDUs in this study were aware of their serostatus. Expanded availability of HCV screening with high quality counseling is clearly needed for this population to promote the health of chronically HCV-infected IDUs and to decrease risk among injectors susceptible to acquiring or transmitting HCV.


Expression and secretion of TNF-α in mouse taste buds: a novel function of a specific subset of type II taste cells.
Taste buds are chemosensory structures widely distributed on the surface of the oral cavity and larynx. Taste cells, exposed to the oral environment, face great challenges in defense against potential pathogens. While immune cells, such as T-cells and macrophages, are rarely found in taste buds, high levels of expression of some immune-response-associated molecules are observed in taste buds. Yet, the cellular origins of these immune molecules such as cytokines in taste buds remain to be determined. Here, we show that a specific subset of taste cells selectively expresses high levels of the inflammatory cytokine tumor necrosis factor-α (TNF-α). Based on immuno-colocalization experiments using taste-cell-type markers, the TNF-α-producing cells are predominantly type II taste cells expressing the taste receptor T1R3. These cells can rapidly increase TNF-α production and secretion upon inflammatory challenges, both in vivo and in vitro. The lipopolysaccharide (LPS)-induced TNF-α expression in taste cells was completely eliminated in TLR2(-/-)/TLR4(-/-) double-gene-knockout mice, which confirms that the induction of TNF-α in taste buds by LPS is mediated through TLR signaling pathways. The taste-cell-produced TNF-α may contribute to local immune surveillance, as well as regulate taste sensation under normal and pathological conditions.


Hormone balance and abiotic stress tolerance in crop plants.
Plant hormones play central roles in the ability of plants to adapt to changing environments, by mediating growth, development, nutrient allocation, and source/sink transitions. Although ABA is the most studied stress-responsive hormone, the role of cytokinins, brassinosteroids, and auxins during environmental stress is emerging. Recent evidence indicated that plant hormones are involved in multiple processes. Cross-talk between the different plant hormones results in synergetic or antagonic interactions that play crucial roles in response of plants to abiotic stress. The characterization of the molecular mechanisms regulating hormone synthesis, signaling, and action are facilitating the modification of hormone biosynthetic pathways for the generation of transgenic crop plants with enhanced abiotic stress tolerance.


Spinach in the teeth: How ego- and allocentric perspectives modulate neural correlates of embarrassment in the face of others' public mishaps.
Humans experience vicarious embarrassment when they observe other's mishaps in public settings, even when the protagonist is not embarrassed at all. Though neural correlates of vicarious embarrassment have been studied before, it is yet poorly understood how they are influenced by egocentric or allocentric processes of perspective-taking. In the present study we examined the effects of deliberate allocentric and egocentric perspectives during the evaluation of others' public mishaps that pose a threat to the protagonist's reputation. Forty-three participants were shown sketches depicting a protagonist's mishaps and were asked to rate either their own vicarious embarrassment as observers (egocentric perspective) or the protagonist's embarrassment (allocentric perspective). Using functional magnetic resonance imaging, we found that observing others' mishaps engaged the anterior insula, anterior cingulate cortex and medial prefrontal cortex, irrespective of the adopted mental perspective. Further, as part of the mentalizing network, the right middle temporal gyrus and right temporo-parietal junction were exclusively engaged when participants adopted an allocentric perspective while observing others' mishaps. Activation within bilateral areas of the inferior parietal cortex extending to the somatosensory cortex varied as a function of the protagonist's awareness of the blunder and the adopted perspective. In this study, we for the first time dissociate regions within the mentalizing network that contribute to a rather spontaneous versus a rather deliberate and motivated act of understanding other's mental states in the context of vicarious embarrassment.


Geographic patterns of childhood insulin-dependent diabetes mellitus. Diabetes Epidemiology Research International Group.
Population-based registries of insulin-dependent diabetes mellitus (IDDM) worldwide have reached the critical mass needed to investigate global patterns of the disease. International collaboration of 24 registries from 15 countries resulted in the first set of standardized incidence measures among divergent areas and ethnic groups. The average annual age-adjusted incidence under age 15 yr ranged from 1.7/100,000 person-yr in Hokkaido, Japan, to 29.5/100,000 person-yr in Finland during the years 1978-1980. The geographic differences in IDDM in childhood are rarely seen among chronic diseases. It appears that the risk for IDDM is determined by factor(s) correlated to the average yearly temperature of environment and to the ethnicity of the population at risk.


The effect of fiber supplementation on irritable bowel syndrome: a systematic review and meta-analysis.
Fiber has been used for many years to treat irritable bowel syndrome (IBS). This approach had fallen out of favor until a recent resurgence, which was based on new randomized controlled trial (RCT) data that suggested it might be effective. We have previously conducted a systematic review of fiber in IBS, but new RCT data for fiber therapy necessitate a new analysis; thus, we have conducted a systematic review of this intervention. MEDLINE, EMBASE, and the Cochrane Controlled Trials Register were searched up to December 2013. Trials recruiting adults with IBS, which compared fiber supplements with placebo, control therapy, or "usual management", were eligible. Dichotomous symptom data were pooled to obtain a relative risk (RR) of remaining symptomatic after therapy as well as number needed to treat (NNT) with a 95% confidence interval (CI). We identified 14 RCTs involving 906 patients that had evaluated fiber in IBS. There was a significant benefit of fiber in IBS (RR=0.86; 95% CI 0.80-0.94 with an NNT=10; 95% CI=6-33). There was no significant heterogeneity between results (I(2)=0%, Cochran Q=13.85 (d.f.=14), P=0.46). The benefit was only seen in RCTs on soluble fiber (RR=0.83; 95% CI 0.73-0.94 with an NNT=7; 95% CI 4-25) with no effect seen with bran (RR=0.90; 95% CI 0.79-1.03). Soluble fiber is effective in treating IBS. Bran did not appear to be of benefit, although we did not uncover any evidence of harm from this intervention, as others have speculated from uncontrolled data.


Exchanges of genomic domains between poliovirus and other cocirculating species C enteroviruses reveal a high degree of plasticity.
The attenuated Sabin strains contained in the oral poliomyelitis vaccine are genetically unstable, and their circulation in poorly immunized populations can lead to the emergence of pathogenic circulating vaccine-derived polioviruses (cVDPVs). The recombinant nature of most cVDPV genomes and the preferential presence of genomic sequences from certain cocirculating non-polio enteroviruses of species C (EV-Cs) raise questions about the permissiveness of genetic exchanges between EV-Cs and the phenotypic impact of such exchanges. We investigated whether functional constraints limited genetic exchanges between Sabin strains and other EV-Cs. We bypassed the natural recombination events by constructing 29 genomes containing a Sabin 2 capsid-encoding sequence and other sequences from Sabin 2 or from non-polio EV-Cs. Most genomes were functional. All recombinant viruses replicated similarly in vitro, but recombination modulated plaque size and temperature sensitivity. All viruses with a 5'UTR from Sabin 2 were attenuated in mice, whereas almost all viruses with a non-polio 5'UTR caused disease. These data highlight the striking conservation of functional compatibility between different genetic domains of cocirculating EV-Cs. This aspect is only one of the requirements for the generation of recombinant cVDPVs in natural conditions, but it may facilitate the generation of viable intertypic recombinants with diverse phenotypic features, including pathogenicity.


Naphthalimides in fluorescent imaging of tumor hypoxia - An up-to-date review.
Hypoxia is a distinctive characteristic of advanced solid malignancies that results from a disparity between oxygen supply and its consumption. The degree of hypoxia is believed to have adverse prognostic significance. Therefore detecting cellular hypoxia can potentially offer insights into the grade of tumour as well as its evolution towards a progressive malignant phenotype, which clinically translates to greater metastatic potential and treatment resistance. Fluorescence imaging to visualize hypoxia in biological systems is a minimally-invasive method. Recently there are several reports on interdisciplinary research that aims at developing functional probes that can be efficiently used for non-invasive imaging of hypoxic tumours. Upregulated levels of nitroreductase (NTR) is detected in hypoxic solid malignancies, and this characteristic feature is increasingly utilized in the development of NTR-targeted fluorescent molecules to selectively sense hypoxia in vivo. The present review summarizes various reports published on the design concepts of nitro naphthalimide-based bio-reductive fluorescent sensors that can be applied noninvasively to image hypoxia in cancer.


Cognitive aspects of frailty: mechanisms behind the link between frailty and cognitive impairment.
Whereas physical impairment is the main hallmark of frailty, evidence suggests that other dimensions, such as psychological, cognitive and social factors also contribute to this multidimensional condition. Cognition is now considered a relevant domain of frailty. Cognitive and physical frailty interact: cognitive problems and dementia are more prevalent in physically frail individuals, and those with cognitive impairment are more prone to become frail. Disentangling the relationship between cognition and frailty may lead to new intervention strategies for the prevention and treatment of both conditions. Both frailty and cognitive decline share common potential mechanisms. This review examines the relationship between frailty and cognitive decline and explores the role of vascular changes, hormones, vitamin D, inflammation, insulin resistance, and nutrition in the development of physical frailty and cognitive problems, as potential underlying mechanisms behind this link. Dual tasking studies may be a useful way to explore and understand the relation between cognitive and physical frailty. Further studies are needed to elucidate this complex relation to improve the outcomes of frailty.


The Impact of Physical Activity and Function on Falls in Assisted Living Residents.
The purpose of this study was to describe physical activity and function of older adults in assisted living communities and test the association between moderate and vigorous activity and falls. This study used baseline data from 393 participants from the first two cohorts in the Function-Focused Care in Assisted Living Using the Evidence Integration Triangle study. The majority of participants were female (N = 276, 70%) and White (N = 383, 97%) with a mean age of 87 years (SD = 7). Controlling for age, cognition, gender, setting, and function, the time spent in moderate or vigorous levels of physical activity was associated with having a fall in the prior 4 months. Those who engaged in more moderate physical activity were 0.6% less likely to have a fall (OR = 0.994, Wald statistic = 5.54, p = .02), and those who engaged in more vigorous activity were 2% less likely to have a fall (OR = 0.980, Wald statistic = 3.88, p = .05).


Final report of the safety assessment of Alcohol Denat., including SD Alcohol 3-A, SD Alcohol 30, SD Alcohol 39, SD Alcohol 39-B, SD Alcohol 39-C, SD Alcohol 40, SD Alcohol 40-B, and SD Alcohol 40-C, and the denaturants, Quassin, Brucine Sulfate/Brucine, and Denatonium Benzoate.
Alcohol Denat. is the generic term used by the cosmetics industry to describe denatured alcohol. Alcohol Denat. and various specially denatured (SD) alcohols are used as cosmetic ingredients in a wide variety of products. Many denaturants have been previously considered, on an individual basis, as cosmetic ingredients by the Cosmetic Ingredient Review (CIR) Expert Panel, whereas others, including Brucine and Brucine Sulfate, Denatonium Benzoate, and Quassin, have not previously been evaluated. Quassin is a bitter alkaloid obtained from the wood of Quassia amara. Quassin has been used as an insect antifeedant and insecticide and several studies demonstrate its effectiveness. At oral doses up to 1000 mg/kg using rats, Quassin was not toxic in acute and short-term tests, but some reversible piloerection, decrease in motor activity, and a partial loss of righting reflex were found in mice at 500 mg/kg. At 1000 mg/kg given intraperitoneally (i.p.), all mice died within 24 h of receiving treatment. In a cytotoxicity test with brine shrimp, 1 mg/ml of Quassin did not possess any cytotoxic or antiplasmodial activity. Quassin administered to rat Leydig cells in vitro at concentrations of 5-25 ng/ml inhibited both the basal and luteinizing hormone (LH)-stimulated testosterone secretion in a dose-related fashion. Quassin at doses up to 2.0 g/kg in drinking water using rats produced no significant effect on the body weights, but the mean weights of the testes, seminal vesicles, and epididymides were significantly reduced, and the weights of the anterior pituitary glands were significantly increased. The sperm counts and levels of LH, follicle-stimulating hormone (FSH), and testosterone were significantly lower in groups treated with Quassin. Brucine is a derivative of 2-hydroxystrychnine. Swiss-Webster mice given Brucine base, 30 ml/kg, had an acute oral LD(50) of 150 mg/kg, with central nervous system depression followed by convulsions and seizures in some cases. In those animals that died, respiratory arrest was the cause. The acute i.p. LD(50) for 15 ml/kg of Brucine base was 62.0 mg/kg, with central nervous system depression prior to the onset of convulsions, just as with oral Brucine. The acute intravenous (i.v.) LD(50) was 12.0 mg/kg. Brucine was nonmutagenic in an Ames assay at levels up to 6666 mu g/plate, with and without metabolic activation. In a repeat-insult patch test, for a hair care product containing 47% SD Alcohol 40 (95%), it was reported that Brucine Sulfate may be considered a nonprimary irritant and a nonprimary sensitizer. Three different sunscreen products (35% SD Alcohol 40-B, 72.4% SD Alcohol 40, and 74.5% SD Alcohol 40) did not show any signs of photoallergy in human subjects. Also, these three formulas did not exhibit any evidence of phototoxicity in humans. Denatonium Benzoate is a bitter substance detectable at a concentration of 10 ppb, discernibly bitter at 50 ppb, and unpleasantly bitter at 10 ppm. The distribution of topically applied lidocaine, a topical anesthetic chemically related to Denatonium Benzoate demonstrated that virtually no lidocaine appears in the plasma, suggesting that the larger Denatonium Benzoate molecule also would have little or no systemic exposure. Denatonium Benzoate (0.1%) did not show adverse effects in 10 rats in an acute inhalation toxicity test and 0.005% to 0.05% was nonirritating to ocular mucosa in 6 albino rabbits. The acute oral LD(50) for the male rats was 640 mg/kg and for females, 584 mg/kg. The LD(50) for the male rabbits was 508 mg/kg and for the female rabbits, 640 mg/kg. In two chronic toxicity studies, Denatonium Benzoate was administered (by gavage) at 1.6, 8, and 16 mg/kg/day, one using cynomologus monkeys and the other rats, resulted in no compound-related toxicity. The toxicity of SD Alcohols has also been tested, with implications for the particular denaturant used. An irritation test of 55.65% SD Alcohol 40-B denatured with Denatonium Benzoate using rabbits produced minimal effects. A spray formula containing 12% SD Alcohol 40-B was found to be nonirritating when evaluated for vaginal mucosal irritation in New Zealand white rabbits. Cosmetic formulations containing SD Alcohol 40-B (denatured with Denatonium Benzoate) were not sensitizers in repeated insult patch tests. A gel formula containing 29% SD Alcohol 40-B and a spray liquid containing 12% SD Alcohol 40-B did not induce photoallergy, dermal sensitization, or phototoxic response in human subjects. Although the absorption of ethanol (aka Alcohol for purposes of cosmetic ingredient labeling) occurs through skin, ethanol does not appear to affect the integrity of the skin barrier nor reach a very high systemic concentration following dermal exposure. Ethanol may be found in the bloodstream as a result of inhalation exposure and ingestion. Topically applied, ethanol can act as a penetration enhancer. Most of the systemic toxicity of ethanol appears to be associated with chronic abuse of alcohol. Although ethanol is denatured to make it unfit for consumption, there have been reports of intentional and unintentional consumption of products containing denatured alcohol. Ethanol is a reproductive and developmental toxicant. Ethanol is genotoxic in some test systems and it has been proposed that the genotoxic effects of ethanol are mediated via its metabolite, acetaldehyde. A brief summary is provided of the effects of chronic ingestion of alcohol including intoxication, liver damage, brain damage, and possible carcinogenicity. The CIR Expert Panel recognizes that certain ingredients in this group are reportedly used in a given product category, but the concentration of use is not available. Because dermal application or inhalation of cosmetic products containing these ingredients will not produce significant systemic exposure to ethanol, the CIR Expert Panel concluded that safety of the ingredients should be predicated on the safety of the denaturants used. The Panel considered that the adverse effects known to be associated with Alcohol ingestion included in this safety assessment do not suggest a concern for Alcohol Denat. or SD Alcohols because of the presence of the denaturants, which are added for the express purpose of making the Alcohol unpotable. The CIR Expert Panel has previously conducted safety assessments of t-Butyl Alcohol, Diethyl Phthalate, Methyl Alcohol, Salicylic Acid, Sodium Salicylate, and Methyl Salicylate, in which each was affirmed safe or safe with qualifications. Given their use as denaturants are at low concentrations of use in Alcohol, the CIR Expert Panel determined that Alcohol Denat. denatured with t-Butyl Alcohol, Diethyl Phthalate, Methyl Alcohol, Salicylic Acid, Sodium Salicylate, and Methyl Salicylate is safe as used in cosmetic formulations with no qualifications. Likewise, because they are denatured with either t-Butyl Alcohol, Diethyl Phthalate, or Methyl Alcohol, SD Alcohols 3-A, 30, 39-B, 39-C, and 40-C all are considered safe as used. The Panel considered the available data for Denatonium Benzoate and SD Alcohol 40-B to be sufficient to support the safety of these ingredients in cosmetics. Denatonium Benzoate is sufficiently bitter that it is an effective denaturant at only 0.0006%. The Panel recognized that data on dermal penetration of Denatonium Benzoate were not available, but considered that the available data on lidocaine, a smaller structurally related chemical, indicates that dermal exposure does not result in measurable systemic exposure. The available data, however, were not sufficient to support the safety of Quassin, Brucine, and Brucine Sulfate, Alcohol Denat. denatured with those denaturants, or SD Alcohol 39 and SD Alcohol 40 (SD Alcohols denatured with Quassin, Brucine, and/or Brucine Sulfate), and in order for the Expert Panel to reach a conclusion for these denaturants, additional data are needed.


How to improve the signal-to-noise ratio for circular polarizers consisting of helical metamaterials?
In this paper, we proposed new structured metamaterials with multi-helical nanowires to construct circular polarizers with higher S/N ratios. Compared with the single-helical ones reported by J. K. Gansel et al. [Science 325, 1513 (2009), Opt. Express 18, 1059 (2010)], which has a lower S/N ratio (~10 dB) due to the high intensity conversion, the circular polarizers with the multi-helical structures have average two orders higher S/N ratios (~35 dB). Simultaneously, other optical performances, such as operation bands, average extinction ratios, are also improved.


Knowledge, attitudes, and acceptability of direct-acting antiviral hepatitis C treatment among people incarcerated in jail: A qualitative study.
While U.S. jails are critical sites for engagement in HCV care, short lengths-of-stay often do not permit treatment in jail. Therefore, linkage to HCV care after incarceration is crucial. However, little is known about HCV treatment acceptability among justice-involved individuals in U.S. jails. The goal of this study was to understand knowledge, attitudes, and acceptability of HCV treatment among people living with HCV in the New York City (NYC) jail system. We recruited 36 HCV-antibody-positive individuals in the NYC jails using clinical data reports and performed semi-structured interviews to explore participants' attitudes toward HCV treatment in jail and following return to the community. We continued interviews until reaching thematic saturation and analyzed interviews using an inductive, thematic approach. Participants were mostly male, Latina/o, with a mean age of 40 years. Nearly all were aware they were HCV antibody-positive. Two thirds of participants had some awareness of the availability of new HCV therapies. Key themes included: 1) variable knowledge of new HCV therapies affecting attitudes toward HCV treatment, 2) the importance of other incarcerated individuals in communicating HCV-related knowledge, 3) vulnerability during incarceration and fear of treatment interruption, 4) concern for relapse to active drug use and HCV reinfection, 5) competing priorities (such as other medical comorbidities, ongoing substance use, and housing), 6) social support and the importance of family. Patient-centered approaches to increase treatment uptake in jail settings should focus on promoting HCV-related knowledge including leveraging peers for knowledge dissemination. In addition, transitional care programs should ensure people living with HCV in jail have tailored discharge plans focused on competing priorities such as housing instability, social support, and treatment of substance use disorders.


Sedentary Thresholds for Accelerometry-Based Mean Amplitude Deviation and Electromyography Amplitude in 7-11 Years Old Children.
We investigated the ability of energy expenditure, movement sensing, and muscle activity to discriminate sedentary and non-sedentary activities in children. Thirty-five 7-11-year-old children participated in the study. Simultaneous assessment of oxygen uptake (V̇O2), triaxial accelerometry, and thigh muscle electromyography (EMG) were performed during eight different sedentary and non-sedentary activities including lying down, sitting-, standing-, and walking-related activities, which were performed in a random order. Mean values of V̇O2, accelerometry, and EMG from the concurrent 2 min epochs during each activity were computed. Resting energy expenditure (REE) was measured during 30 min supine rest. Directly measured metabolic equivalent of tasks (METs, V̇O2 in activities/V̇O2 in REE) were calculated for each activity. Mean amplitude deviation (MAD) was computed for accelerometry. EMG was normalized for mean muscle activity during self-paced walking. The classification accuracy of METs, MAD, and EMG to discriminate sedentary activities from physical activities was investigated by receiver operating characteristic curves and optimal cut-offs based on maximal sensitivity and specificity. Mean (SD) REE was 5.0 ± 0.8 ml/kg/min. MET, MAD, and EMG values ranged from 1.0 to 4.9, 0.0020 to 0.4146 g, and 4.3 to 133.9% during lying down and walking at 6 km/h, respectively. Optimal cut-offs to discriminate sedentary activities from non-sedentary activities were 1.3 for METs (sensitivity = 82%, specificity = 88%), 0.0033 g for MAD (sensitivity = 80%, specificity = 91%), and 11.9% for EMG (sensitivity = 79%, specificity = 92%). In conclusion, this study provides applicable thresholds to differentiate sitting and standing and sedentary and non-sedentary activities based on METs, MAD, and EMG in young children.


Selective deficit in spatial memory strategies contrast to intact response strategies in patients with schizophrenia spectrum disorders tested in a virtual navigation task.
Spatial memory is impaired among persons with schizophrenia (SCZ). However, different strategies may be used to solve most spatial memory and navigation tasks. This study investigated the hypothesis that participants with schizophrenia-spectrum disorders (SSD) would demonstrate differential impairment during acquisition and retrieval of target locations when using a hippocampal-dependent spatial strategy, but not a response strategy, which is more associated with caudate function. Healthy control (CON) and SSD participants were tested using the 4-on-8 virtual maze (4/8VM), a virtual navigation task designed to differentiate between participants' use of spatial and response strategies. Consistent with our predictions, SSD participants demonstrated a differential deficit such that those who navigated using a spatial strategy made more errors and took longer to locate targets. In contrast, SSD participants who spontaneously used a response strategy performed as well as CON participants. The differential pattern of spatial-memory impairment in SSD provides only indirect support for underlying hippocampal dysfunction. These findings emphasize the importance of considering individual strategies when investigating SSD-related memory and navigation performance. Future cognitive intervention protocols may harness SSD participants' intact ability to navigate using a response strategy and/or train the deficient ability to navigate using a spatial strategy to improve navigation and memory abilities in participants with SSD.


Structural and functional studies of the human phosphoribosyltransferase domain containing protein 1.
Human hypoxanthine-guanine phosphoribosyltransferase (HPRT) (EC 22.214.171.124) catalyzes the conversion of hypoxanthine and guanine to their respective nucleoside monophosphates. Human HPRT deficiency as a result of genetic mutations is linked to both Lesch-Nyhan disease and gout. In the present study, we have characterized phosphoribosyltransferase domain containing protein 1 (PRTFDC1), a human HPRT homolog of unknown function. The PRTFDC1 structure has been determined at 1.7 Å resolution with bound GMP. The overall structure and GMP binding mode are very similar to that observed for HPRT. Using a thermal-melt assay, a nucleotide metabolome library was screened against PRTFDC1 and revealed that hypoxanthine and guanine specifically interacted with the enzyme. It was subsequently confirmed that PRTFDC1 could convert these two bases into their corresponding nucleoside monophosphate. However, the catalytic efficiency (k(cat)/K(m)) of PRTFDC1 towards hypoxanthine and guanine was only 0.26% and 0.09%, respectively, of that of HPRT. This low activity could be explained by the fact that PRTFDC1 has a Gly in the position of the proposed catalytic Asp of HPRT. In PRTFDC1, a water molecule at the position of the aspartic acid side chain position in HPRT might be responsible for the low activity observed by acting as a weak base. The data obtained in the present study indicate that PRTFDC1 does not have a direct catalytic role in the nucleotide salvage pathway.


Trimethylamine N-Oxide: The Good, the Bad and the Unknown.
Trimethylamine N-oxide (TMAO) is a small colorless amine oxide generated from choline, betaine, and carnitine by gut microbial metabolism. It accumulates in the tissue of marine animals in high concentrations and protects against the protein-destabilizing effects of urea. Plasma level of TMAO is determined by a number of factors including diet, gut microbial flora and liver flavin monooxygenase activity. In humans, a positive correlation between elevated plasma levels of TMAO and an increased risk for major adverse cardiovascular events and death is reported. The atherogenic effect of TMAO is attributed to alterations in cholesterol and bile acid metabolism, activation of inflammatory pathways and promotion foam cell formation. TMAO levels increase with decreasing levels of kidney function and is associated with mortality in patients with chronic kidney disease. A number of therapeutic strategies are being explored to reduce TMAO levels, including use of oral broad spectrum antibiotics, promoting the growth of bacteria that utilize TMAO as substrate and the development of target-specific molecules with varying level of success. Despite the accumulating evidence, it is questioned whether TMAO is the mediator of a bystander in the disease process. Thus, it is important to undertake studies examining the cellular signaling in physiology and pathological states in order to establish the role of TMAO in health and disease in humans.


Factors associated with suicidal ideation among medical students during the initial phase of the COVID-19 pandemic in Peru: A multicenter study.
We aimed to describe the prevalence and factors associated with suicidal ideation in a sample of 1238 medical students from different medical schools in Peru based on question 9 of the Patient Health Questionnaire (PHQ-9). Our results revealed that 17.9% of the participants had suicidal ideation. Furthermore, using logistic regression, we found that not practicing any religion, the presence of clinically significant depression, and the presence of clinically significant anxiety were statistically related to the presence of suicidal ideation. Our results indicate that suicidal ideation was highly prevalent in the sample of medical students studied.


Exploring the self-assembly and energy transfer of dynamic supramolecular iridium-porphyrin systems.
We present the first examples of dynamic supramolecular systems composed of cyclometalated Ir(iii) complexes of the form of [Ir(C^N)2(N^N)]PF6 (where C^N is mesppy = 2-phenyl-4-mesitylpyridinato and dFmesppy = 2-(4,6-difluorophenyl)-4-mesitylpyridinato and N^N is 4,4':2',2'':4'',4'''-quaterpyridine, qpy) and zinc tetraphenylporphyrin (ZnTPP), assembled through non-covalent interactions between the distal pyridine moieties of the qpy ligand located on the iridium complex and the zinc of the ZnTPP. The assemblies have been comprehensively characterized by a series of analytical techniques (1H NMR titration experiments, 2D COSY and HETCOR NMR spectra and low temperature 1H NMR spectroscopy) and the crystal structures have been elucidated by X-ray diffraction. The optoelectronic properties of the assemblies and the electronic interaction between the iridium and porphyrin chromophoric units have been explored with detailed photophysical measurements, supported by time-dependent density functional theory (TD-DFT) calculations.


Salmeterol: a long-acting beta 2-agonist.
Salmeterol xinafoate is a potent and highly selective beta 2-adrenoreceptor agonist with a duration of action greater than 12 hours. When inhaled twice daily in the management of chronic asthma, it results in improved lung function, reduces acute asthmatic exacerbations, and improves the patient's quality of life. This agent has shown particular benefit for patients who continue to have symptomatic asthma despite the regular use of inhaled corticosteroid therapy and the frequent use of a short-acting beta 2-agonist. Although there is some evidence that salmeterol induces some tolerance to the bronchoprotective effect of beta 2-agonist therapy, improvement in lung function and asthma symptoms scores, during both the daytime and nighttime, are sustained. Importantly, patients must be educated in the proper use of salmeterol; for many asthmatics, this medication should be administered with inhaled or oral corticosteroid therapy, and salmeterol should not be used for rescue bronchodilation. When used properly, salmeterol is an effective and safe adjunctive therapy in the management of chronic asthma in adolescents and adults.


When is irony influenced by communicative constraints? ERP evidence supporting interactive models.
Distinct theoretical proposals have described how communicative constraints (contextual biases, speaker identity) impact verbal irony processing. Modular models assume that social and contextual factors have an effect at a late stage of processing. Interactive models claim that contextual biases are considered early on. The constraint-satisfaction model further assumes that speaker's and context's characteristics can compete at early stages of analysis. The present ERP study teased apart these models by testing the impact of context and speaker features (i.e., speaker accent) on irony analysis. Spanish native speakers were presented with Spanish utterances that were ironic or literal. Each sentence was preceded by a negative or a positive context. Each story was uttered in a native or a foreign accent. Results showed that contextual biases and speaker accent interacted as early as 150 ms during irony processing. Greater N400-like effects were reported for ironic than literal sentences only with positive contexts and native accent, possibly suggesting semantic difficulties when non-prototypical irony was produced by natives. A P600 effect of irony was also reported indicating inferential processing costs. The results support the constraint-satisfaction model and suggest that multiple sources of information are weighted and can interact from the earliest stages of irony analysis.


Hiccups attributable to syringobulbia and/or syringomyelia associated with a Chiari I malformation: case report.
Approximately 20 to 50% of patients with syringomyelia associated with Chiari malformations exhibit cranial nerve or cerebellar symptoms. However, hiccups represent a rare clinical manifestation of this disorder. We report a case of intractable hiccups resulting from syringobulbia associated with a Chiari I malformation, which was successfully treated with foramen magnum decompression. We report the case of a patient who presented with syringomyelia and syringobulbia associated with a Chiari I malformation, manifested as intractable hiccups and neurological deficits. Magnetic resonance imaging scans demonstrated syringobulbia in the dorsal medullary region and a large cervical syrinx from C2 to C6-C7, associated with a Chiari I malformation. Foramen magnum decompression and a C1 laminectomy were performed. One month later, the intractable hiccups disappeared and the neurological symptoms demonstrated improvement. Postoperative magnetic resonance imaging scans demonstrated enlargement of the subarachnoid space in the posterior fossa and disappearance of the syringobulbia. There has been no recurrence of intractable hiccups and syringobulbia in 6 months after surgery. Magnetic resonance imaging of the brainstem is an important diagnostic procedure for intractable hiccups, because syringobulbia associated with a Chiari malformation represents a surgically treatable disorder, although the incidence is low.


UTLS water vapour from SCIAMACHY limb measurementsV3.01 (2002-2012).
The SCanning Imaging Absorption spectroMeter for Atmospheric CHartographY (SCIAMACHY) aboard the Envisat satellite provided measurements from August 2002 until April 2012. SCIAMACHY measured the scattered or direct sunlight using different observation geometries. The limb viewing geometry allows the retrieval of water vapour at about 10-25 km height from the near-infrared spectral range (1353-1410 nm). These data cover the upper troposphere and lower stratosphere (UTLS), a region in the atmosphere which is of special interest for a variety of dynamical and chemical processes as well as for the radiative forcing. Here, the latest data version of water vapour (V3.01) from SCIAMACHY limb measurements is presented and validated by comparisons with data sets from other satellite and in situ measurements. Considering retrieval tests and the results of these comparisons, the V3.01 data are reliable from about 11 to 23 km and the best results are found in the middle of the profiles between about 14 and 20 km. Above 20 km in the extra tropics V3.01 is drier than all other data sets. Additionally, for altitudes above about 19 km, the vertical resolution of the retrieved profile is not sufficient to resolve signals with a short vertical structure like the tape recorder. Below 14 km, SCIAMACHY water vapour V3.01 is wetter than most collocated data sets, but the high variability of water vapour in the troposphere complicates the comparison. For 14-20 km height, the expected errors from the retrieval and simulations and the mean differences to collocated data sets are usually smaller than 10 % when the resolution of the SCIAMACHY data is taken into account. In general, the temporal changes agree well with collocated data sets except for the Northern Hemisphere extratropical stratosphere, where larger differences are observed. This indicates a possible drift in V3.01 most probably caused by the incomplete treatment of volcanic aerosols in the retrieval. In all other regions a good temporal stability is shown. In the tropical stratosphere an increase in water vapour is found between 2002 and 2012, which is in agreement with other satellite data sets for overlapping time periods.


The Impact of Pulmonary Rehabilitation on Chronic Pain in People with COPD.
Chronic pain affects up to 88% of people with chronic obstructive pulmonary disease (COPD) and has been associated with comorbidities. However, with pain not evaluated during pulmonary rehabilitation (PR) assessments, it is unclear whether PR impacts pain intensity and coping ability. This study aimed to 1) determine the effect of PR on pain qualities, coping behavior and psychological symptoms in those with COPD and chronic pain; and 2) assess the impact of PR on exercise capacity and quality of life in individuals with COPD and chronic pain compared to those without pain. Patients with COPD and comorbidities enrolling in outpatient PR were assessed for chronic pain. Those with chronic pain completed the Brief Pain Inventory, Coping Strategies Questionnaire-24, Fear Avoidance Behavior Questionnaire and measures of anxiety and depression. Changes in HRQOL and 6-minute walk distance (6MWD) following PR were compared between participants with and without chronic pain. Thirty-four participants with chronic pain and 34 participants without pain were included (mean ± SD, FEV1 47 ± 19% predicted). In those with chronic pain, PR did not affect pain intensity (median[IQR] pre/post PR 3[2-5] vs. 4[2-6] points, p = 0.21), anxiety (7[2-9] vs. 5[3-8] points, p = 0.82) or depression (4[2-8] vs. 3[1-6] points, p = 0.38) and did not change pain coping strategies. Both groups improved in 6MWD (mean difference [95% CI] 17[-39 to 72] m), and those without pain had greater improvement in mastery (p = 0.013). PR was effective in patients with moderate to severe COPD whether or not they reported chronic pain at the time of their initial assessment.


White matter microstructure mediates the relationship between cardiorespiratory fitness and spatial working memory in older adults.
White matter structure declines with advancing age and has been associated with a decline in memory and executive processes in older adulthood. Yet, recent research suggests that higher physical activity and fitness levels may be associated with less white matter degeneration in late life, although the tract-specificity of this relationship is not well understood. In addition, these prior studies infrequently associate measures of white matter microstructure to cognitive outcomes, so the behavioral importance of higher levels of white matter microstructural organization with greater fitness levels remains a matter of speculation. Here we tested whether cardiorespiratory fitness (VO2max) levels were associated with white matter microstructure and whether this relationship constituted an indirect pathway between cardiorespiratory fitness and spatial working memory in two large, cognitively and neurologically healthy older adult samples. Diffusion tensor imaging was used to determine white matter microstructure in two separate groups: Experiment 1, N=113 (mean age=66.61) and Experiment 2, N=154 (mean age=65.66). Using a voxel-based regression approach, we found that higher VO2max was associated with higher fractional anisotropy (FA), a measure of white matter microstructure, in a diverse network of white matter tracts, including the anterior corona radiata, anterior internal capsule, fornix, cingulum, and corpus callosum (PFDR-corrected<.05). This effect was consistent across both samples even after controlling for age, gender, and education. Further, a statistical mediation analysis revealed that white matter microstructure within these regions, among others, constituted a significant indirect path between VO2max and spatial working memory performance. These results suggest that greater aerobic fitness levels are associated with higher levels of white matter microstructural organization, which may, in turn, preserve spatial memory performance in older adulthood.


Elastin-derived peptides induce inflammatory responses through the activation of NF-κB in human ligamentum flavum cells.
The formation of fibrotic tissue in the ligamentum flavum (LF) is usually preceded by breakdown of elastic fibers. Elastin-derived peptides (EDPs) from breakdown of elastic fibers display a wide range of biological activities in a variety of cells, but there is minimal information regarding the involvement in the processes of LF hypertrophy. The aim of this study is to elucidate the effects of EDPs on cultured human LF cells and to investigate their molecular and biochemical mechanisms. Human LF cells were obtained from 18 patients who underwent lumbar spine surgery. After treatment with different concentrations of EDPs with or without specific inhibitors in culture medium, the viability and proliferation of LF cells, genes expression, and the signaling pathways were evaluated and analyzed. It was found that 50 μg/ml EDPs significantly increased cell proliferation and synthesis of prostaglandin E(2). The gene expression and protein production of proinflammatory cytokines, including interleukin-1α (IL-1α), IL-1β, and IL-6, were also upregulated. The levels of p-ERK (extracellular signal-regulated kinase) and NF-κB increased immediately following EDP treatment and sustained up to 90 min. It was also found that NF-κB inhibitor, but not ERK1/2 inhibitor, attenuated EDP-dependent induction of IL-1α, IL-1β, and IL-6 expression, indicating that NF-κB pathways are required for EDP-induced IL-1α, IL-1β, and IL-6 gene expression in human LF cells. The results of this in vitro experiment suggest that EDPs do induce inflammatory responses in human LF cells and plays the key role in the development of LF hypertrophy.


A novel in vivo method for isolating antibodies from a phage display library by neuronal retrograde transport selectively yields antibodies against p75(NTR.).
The neurotrophin receptor p75(NTR) is utilized by a variety of pathogens to gain entry into the central nervous system (CNS). We tested if this entry portal might be exploited using a phage display library to isolate internalizing antibodies that target the CNS in vivo. By applying a phage library that expressed human single chain variable fragment (scFv) antibodies on their surface to a transected sciatic nerve, we showed that (1) phage conjugated to anti-p75(NTR) antibody or phage scFv library pre-panned against p75(NTR) are internalized by neurons expressing p75(NTR); (2) subsequent retrograde axonal transport separates internalized phage from the applied phage; and, (3) internalized phage can be recovered from a proximal ligature made on a nerve. This approach resulted in 13-fold increase in the number of phage isolated from the injured nerve compared with the starting population, and isolation of 18 unique internalizing p75(NTR) antibodies that were transported from the peripheral nerve into the spinal cord, through the blood-brain barrier. In addition, antibodies recognizing other potentially internalized antigens were identified through in vivo selection using a fully diverse library. Because p75(NTR) expression is upregulated in motor neurons in response to injury and in disease, the p75(NTR) antibodies may have substantial potential for cell-targeted drug/gene delivery. In addition, this novel selection method provides the potential to generate panels of antibodies that could be used to identify further internalization targets, which could aid drug delivery across the blood-brain barrier.


Non-Response to Antibiotic Treatment in Adolescents for Four Common Infections in UK Primary Care 1991-2012: A Retrospective, Longitudinal Study.
We studied non-response rates to antibiotics in the under-reported subgroup of adolescents aged 12 to 17 years old, using standardised criteria representing antibiotic treatment failure. Routine, primary care data from the UK Clinical Practice Research Datalink (CPRD) were used. Annual, non-response rates by antibiotics and by indication were determined. We identified 824,651 monotherapies in 415,468 adolescents: 368,900 (45%) episodes for upper respiratory tract infections (URTIs), 89,558 (11%) for lower respiratory tract infections (LRTIs), 286,969 (35%) for skin/soft tissue infections (SSTIs) and 79,224 (10%) for acute otitis media (AOM). The most frequently prescribed antibiotics were amoxicillin (27%), penicillin-V (24%), erythromycin (11%), flucloxacillin (11%) and oxytetracycline (6%). In 1991, the overall non-response rate was 9.3%: 11.9% for LRTIs, 9.5% for URTIs, 7.1% for SSTIs, 9.7% for AOM. In 2012, the overall non-response rate was 9.2%. Highest non-response rates were for AOM in 1991-1999 and for LRTIs in 2000-2012. Physicians generally prescribed antibiotics to adolescents according to recommendations. Evidence of antibiotic non-response was less common among adolescents during this 22-year study period compared with an all-age population, where the overall non-response rate was 12%.


NABat: A top-down, bottom-up solution to collaborative continental-scale monitoring.
Collaborative monitoring over broad scales and levels of ecological organization can inform conservation efforts necessary to address the contemporary biodiversity crisis. An important challenge to collaborative monitoring is motivating local engagement with enough buy-in from stakeholders while providing adequate top-down direction for scientific rigor, quality control, and coordination. Collaborative monitoring must reconcile this inherent tension between top-down control and bottom-up engagement. Highly mobile and cryptic taxa, such as bats, present a particularly acute challenge. Given their scale of movement, complex life histories, and rapidly expanding threats, understanding population trends of bats requires coordinated broad-scale collaborative monitoring. The North American Bat Monitoring Program (NABat) reconciles top-down, bottom-up tension with a hierarchical master sample survey design, integrated data analysis, dynamic data curation, regional monitoring hubs, and knowledge delivery through web-based infrastructure. NABat supports collaborative monitoring across spatial and organizational scales and the full annual lifecycle of bats.


Molecular epidemiology of Corynebacterium diphtheriae from northwestern Russia and surrounding countries studied by using ribotyping and pulsed-field gel electrophoresis.
A selection of 100 Corynebacterium diphtheriae isolates from asymptomatic carriers and clinical cases from five regions in northwestern Russia were examined. Six additional isolates from patients in Finland and Estonia with epidemiological links to Russia were also examined. All isolates were characterized by biotyping, toxigenicity testing, ribotyping, and pulsed-field gel electrophoresis (PFGE). Hybridization of genomic DNA digested with BstEII revealed five ribotype patterns among the biotype gravis isolates (G1 through G5) and two patterns among the biotype mitis isolates (M1 and M2). PFGE using SfiI was not able to distinguish between ribotypes G1, G2, and G4. The predominant ribotype pattern, G1, found in cases of disease in all the areas studied, appears to be disseminating, in view of the isolates received from imported cases in Finland and Estonia. Among the 106 isolates examined, 68 produced pattern G1 and 24 produced pattern M1. Most of the M1 isolates were from the Leningrad Oblast region. Distinct ribotypes such as G2, G3, G4, G5, and M2 could represent endemic disease.


Industry-relevant magnetron sputtering and cathodic arc ultra-high vacuum deposition system for in situ x-ray diffraction studies of thin film growth using high energy synchrotron radiation.
We present an industry-relevant, large-scale, ultra-high vacuum (UHV) magnetron sputtering and cathodic arc deposition system purposefully designed for time-resolved in situ thin film deposition/annealing studies using high-energy (>50 keV), high photon flux (>10(12) ph/s) synchrotron radiation. The high photon flux, combined with a fast-acquisition-time (<1 s) two-dimensional (2D) detector, permits time-resolved in situ structural analysis of thin film formation processes. The high-energy synchrotron-radiation based x-rays result in small scattering angles (<11°), allowing large areas of reciprocal space to be imaged with a 2D detector. The system has been designed for use on the 1-tonne, ultra-high load, high-resolution hexapod at the P07 High Energy Materials Science beamline at PETRA III at the Deutsches Elektronen-Synchrotron in Hamburg, Germany. The deposition system includes standard features of a typical UHV deposition system plus a range of special features suited for synchrotron radiation studies and industry-relevant processes. We openly encourage the materials research community to contact us for collaborative opportunities using this unique and versatile scientific instrument.


Transplantation of hippocampal cell lines restore spatial learning in rats with ventral subicular lesions.
We have demonstrated in our previous studies that ventral subicular lesion induces neurodegeneration of the hippocampus and produces cognitive impairment in rats. In the present study, the efficacy of transplanted green fluorescent protein (GFP)-labeled hippocampal cell line (H3-GFP) cells in establishing functional recovery in ventral subicular lesioned rats has been evaluated. The survival of H3-GFP transplants and their ability to express trophic factors in vivo were also investigated. Adult male Wistar rats were subjected to selective lesioning of ventral subiculum and were transplanted with H3-GFP cells into the cornu ammonis 1 (CA1) hippocampus. The transplants settled mainly in the dentate gyrus and expressed neurotrophic factors, brain-derived neurotrophic factor (BDNF), and basic fibroblast growth factor (bFGF). The ventral subicular lesioned (VSL) rats with H3-GFP transplants showed enhanced expression of BDNF in the hippocampus and performed well in eight-arm radial maze and Morris water maze tasks. The VSL rats without hippocampal transplants continued to show cognitive impairment in task learning. The present study demonstrated the H3-GFP transplants mediated recovery of cognitive functions in VSL rats. Our study supports the notion of graft meditated host regeneration and functional recovery through trophic support, although these mechanisms require further investigation.


Validation of a Swahili version of the World Health Organization 5-item well-being index among adults living with HIV and epilepsy in rural coastal Kenya.
The purpose of this study was to evaluate the psychometric properties of the World Health Organization's five item well-being index (WHO-5) when administered to adults living with HIV or epilepsy in a rural setting at the coast of Kenya. A case control study design was conducted among 230 adults aged 18-50 years, who comprised 147 cases (63 living with epilepsy and 84 living with HIV) and 83 healthy controls. The participants were administered to a face-to-face interview during which they completed the Swahili version of WHO-5 well-being index, the Major Depression Inventory (MDI) and responded to some items on their socio-demographic characteristics. Analysis to assess internal consistency, construct validity, discriminant validity, and convergent validity of the Swahili version of WHO-5 well-being index was conducted. A multivariate regression was carried out to assess the association between psychological wellbeing (assessed using Swahili version of WHO-5 well-being index) and having a chronic illness (HIV or epilepsy). The Swahili version of WHO-5 well-being index demonstrated good internal consistency with Cronbach alpha ranges of 0.86-0.88 among the three study groups. The tool had good discriminant validity. A one factor structure of the tool was obtained from confirmatory factor analysis (overall Comparative Fit Index = 1.00, Tuckler Lewis Index = 1.01, Root Mean Square of Error Approximation = 0.00). Living with HIV or epilepsy in comparison to being a healthy control was significantly associated with greater odds of having sub-optimal psychological wellbeing. Our findings demonstrate that the Swahili version of WHO-5 well-being index has good psychometric properties and is appropriate for use to evaluate psychological well-being among adults living with chronic conditions such as HIV or epilepsy from a rural low resource setting in Kenya. Given its brevity and ease of use, the Swahili version of WHO-5 well-being index could potentially be used by lay workers and other paraprofessional to monitor psychological well-being among chronically ill adults in resource poor settings.


Social and communication abilities and disabilities in higher functioning individuals with autism spectrum disorders: the Vineland and the ADOS.
The relationship between adaptive functioning (ability) and autism symptomatology (disability) remains unclear, especially for higher functioning individuals with autism spectrum disorder (ASD). This study investigates ability and disability using the Vineland and Autism Diagnostic Observation Schedule (ADOS), respectively, in two clinical samples of children with ASD. Participants included 187 males with VIQ > 70. Vineland scores were substantially below VIQ, highlighting the magnitude of adaptive impairments despite cognitive potential. A weak relationship was found between ability and disability. Negative relationships were found between age and Vineland scores and no relationships were found between age and ADOS scores. Positive relationships were found between IQ and Vineland Communication. Results stress the need for longitudinal studies on ability and disability in ASD and emphasize the importance of adaptive skills intervention.


Tissue micro array analysis of ganglioside N-glycolyl GM3 expression and signal transducer and activator of transcription (STAT)-3 activation in relation to dendritic cell infiltration and microvessel density in non-small cell lung cancer.
Tumor immune escape and angiogenesis contribute to tumor progression, and gangliosides and activation of signal transducer and activator of transcription (STAT)-3 are implicated in these processes. As both are considered as novel therapeutic targets, we assessed the possible association of ganglioside GM3 expression and STAT3 activation with suppression of dendritic cell (DC) activation and angiogenesis in non-small cell lung cancer (NSCLC). Immunohistochemistry was performed on a tissue array to determine N-glycolyl GM3 (GM3) and phosphorylated STAT3 (pSTAT3) expression in 176 primary NSCLC resections. Median values of GM3 and pSTAT3 expression were used as cut off. Microvessel density (MVD) was determined by CD34 staining and morphology. CD1a and CD83 were used to determine infiltrating immature and mature dendritic cells, respectively. 94% and 71% of the NSCLC samples expressed GM3 and nuclear pSTAT3, respectively. Median overall survival was 40.0 months. Both low GM3 expression and high pSTAT3 expression were associated with a worse survival, which reached near significance for GM3 (P = 0.08). Microvessel density (MVD), determined by CD34 staining and morphology, was lower in NSCLC samples with high GM3 expression. CD1a+ cells (immature DCs) were more frequent in NSCLC tissues as compared to peritumoral lung tissue, while CD83+ cells (mature DCs) were more frequent in peritumoral lung tissue. CD83+ DCs were less frequent in NSCLC tissues with high GM3 expression. GM3 and pSTAT3 are widely expressed in NSCLC. Based on CD83 expression, GM3, but not pSTAT3, appeared to be involved in tumor-induced DC suppression. pSTAT3 expression was not associated with MVD, while GM3 might play an anti-angiogenic role.


Final 5-year findings from the phase 3 HELIOS study of ibrutinib plus bendamustine and rituximab in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma.
We report final analysis outcomes from the phase 3 HELIOS study (NCT01611090). Patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma without deletion 17p (n = 578) were randomized 1:1 to 420 mg daily ibrutinib or placebo plus ≤6 cycles of bendamustine plus rituximab (BR), followed by ibrutinib or placebo alone. Median follow-up was 63.7 months. Median investigator-assessed progression-free survival was longer with ibrutinib plus BR (65.1 months) than placebo plus BR (14.3 months; hazard ratio [HR] 0.229 [95% confidence interval (CI) 0.183-0.286]; p < .0001). Despite crossover of 63.3% of patients from the placebo plus BR arm to ibrutinib treatment upon disease progression, ibrutinib plus BR versus placebo plus BR demonstrated an overall survival benefit (HR 0.611 [95% CI 0.455-0.822]; p = .0010; median not reached in either arm). Long-term follow-up data confirm the survival benefit of ibrutinib plus BR over BR alone. Safety profiles were consistent with those known for ibrutinib and BR.


Early antiretroviral therapy in children perinatally infected with HIV: a unique opportunity to implement immunotherapeutic approaches to prolong viral remission.
From the use of antiretroviral therapy to prevent mother-to-child transmission to the possibility of HIV cure hinted at by the Mississippi baby experience, paediatric HIV infection has been pivotal to our understanding of HIV pathogenesis and management. Daily medication and indefinite antiretroviral therapy is recommended for children infected with HIV. Maintenance of life-long adherence is difficult and the incidence of triple-class virological failure after initiation of antiretroviral therapy increases with time. This challenge shows the urgent need to define novel strategies to provide long-term viral suppression that will allow safe interruption of antiretroviral therapy without viral rebound and any associated complications. HIV-infected babies treated within a few days of birth have a unique combination of a very small pool of integrated viruses, a very high proportion of relatively HIV resistant naive T cells, and an unparalleled capacity to regenerate an immune repertoire. These features make this group the optimum model population to investigate the potential efficacy of immune-based therapies. If successful, these investigations could change the way we manage HIV infection.


Blood glutamate grabbing does not reduce the hematoma in an intracerebral hemorrhage model but it is a safe excitotoxic treatment modality.
Recent studies have shown that blood glutamate grabbing is an effective strategy to reduce the excitotoxic effect of extracellular glutamate released during ischemic brain injury. The purpose of the study was to investigate the effect of two of the most efficient blood glutamate grabbers (oxaloacetate and recombinant glutamate oxaloacetate transaminase 1: rGOT1) in a rat model of intracerebral hemorrhage (ICH). Intracerebral hemorrhage was produced by injecting collagenase into the basal ganglia. Three treatment groups were developed: a control group treated with saline, a group treated with oxaloacetate, and a final group treated with human rGOT1. Treatments were given 1 hour after hemorrhage. Hematoma volume (analyzed by magnetic resonance imaging (MRI)), neurologic deficit, and blood glutamate and GOT levels were quantified over a period of 14 days after surgery. The results observed showed that the treatments used induced a significant reduction of blood glutamate levels; however, they did not reduce the hematoma, nor did they improve the neurologic deficit. In the present experimental study, we have shown that this novel therapeutic strategy is not effective in case of ICH pathology. More importantly, these findings suggest that blood glutamate grabbers are a safe treatment modality that can be given in cases of suspected ischemic stroke without previous neuroimaging.


Mechanisms to explain the reverse perivascular transport of solutes out of the brain.
Experimental studies and observations in the human brain indicate that interstitial fluid and solutes, such as amyloid-beta (Abeta), are eliminated from grey matter of the brain along pericapillary and periarterial pathways. It is unclear, however, what constitutes the motive force for such transport within blood vessel walls, which is in the opposite direction to blood flow. In this paper the potential for global pressure differences to achieve such transport are considered. A mathematical model is constructed in order to test the hypothesis that perivascular drainage of interstitial fluid and solutes out of brain tissue is driven by pulsations of the blood vessel walls. Here it is assumed that drainage occurs through a thin layer between astrocytes and endothelial cells or between smooth muscle cells. The model suggests that, during each pulse cycle, there are periods when fluid and solutes are driven along perivascular spaces in the reverse direction to the flow of blood. It is shown that successful drainage may depend upon some attachment of solutes to the lining of the perivascular space, in order to produce a valve-like effect, although an alternative without this requirement is also postulated. Reduction in pulse amplitude, as in ageing cerebral vessels, would prolong the attachment time, encourage precipitation of Abeta peptides in vessel walls, and impair elimination of Abeta from the brain. These factors may play a role in the pathogenesis of cerebral amyloid angiopathy and in the accumulation of Abeta in the brain in Alzheimer's disease.


Insights into the Mechanical Behaviour of a Layered Flexible Tactile Sensor.
This paper shows realizations of a piezoresistive tactile sensor with a low cost screen-printing technology. A few samples were fabricated for different materials used as insulator between the conductive layers and as top layer or cover. Both can be used to tune the sensitivity of the sensor. However, a large influence is also observed of the roughness at the contact interface on the sensitivity and linearity of the output, as well as on mismatching between the outputs from different taxels. The roughness at the contact interface is behind the transduction principle of the sensor, but it also limits its performance if the wavelength of the roughness is comparable or even longer than the size of the contacts. The paper shows experimental results that confirm this relationship and discusses its consequences in sensor response related to the materials chosen for the insulator and the cover. Moreover, simulations with FEA tools and with simple models are used to support the discussions and conclusions obtained from the experimental data. This provides insights into the sensor behaviour that are shared by other sensors based on the same principle.


The effect of vasoactive agents on post-pressure hyperemia.
The cutaneous hyperemic response following the release of direct pressure occlusion lasts much longer than the short-term hyperemia that occurs after proximal arterial occlusion. Post-pressure hyperemia may be an important mechanism to prevent pressure induced injury to the skin. The role of vasoactive mediators in modulating post-pressure hyperemia is unknown. In an effort to better understand this phenomenon, we performed an initial study using microdialysis infusion to measure the effect of several known mediators of vascular response on post-pressure hyperemia. A vise clamp was used to apply direct occlusive pressure to a laser Doppler sensor on the skin surface overlying the microdialysis fiber. Skin blood flow was measured continuously pre, during and post-occlusion while infusing the vasoactive substance or control phosphate buffer. Angiotensin II, Calcitonin gene related peptide and histamine had minimal effect on post pressure blood flow. Conversely, prostaglandin E1, prostaglandin E2, and L-NAME diminished the early phase of the post-occlusion hyperemic response. Perhaps the most profound effect we observed was the decrease in post-occlusive blood flow due to administration of epinephrine, dopamine and prostaglandin F2alpha. In contrast, adenosine and caffeine augmented blood flow post occlusion. In this initial survey study, we have demonstrated differential effects of various vascular mediators on the post-pressure hyperemic phenomenon. Our findings may lead to the development of agents to prevent pressure sores by augmenting the skin blood flow response to locally applied pressure.


Toxicity of copper to early-life stage Kootenai River white sturgeon, Columbia River white sturgeon, and rainbow trout.
White sturgeon (Acipenser transmontanus) populations throughout western North America are in decline, likely as a result of overharvest, operation of dams, and agricultural and mineral extraction activities in their watersheds. Recruitment failure may reflect the loss of early-life stage fish in spawning areas of the upper Columbia River, which are contaminated with metals from effluents associated with mineral-extraction activities. Early-life stage white sturgeon (A. transmontanus) from the Columbia River and Kootenai River populations were exposed to copper during 96-h flow-through toxicity tests to determine their sensitivity to the metal. Similar tests were conducted with rainbow trout (RBT [Oncorhynchus mykiss]) to assess the comparative sensitivity of this species as a surrogate for white sturgeon. Exposures were conducted with a water quality pH 8.1-8.3, hardness 81-119 mg/L as CaCO(2), and dissolved organic carbon 0.2-0.4 mg/L. At approximately 30 days posthatch (dph), sturgeon were highly sensitive to copper with median lethal concentration (LC(50)) values ranging from 4.1 to 6.8 μg/L compared with 36.5 μg/L for 30 dph RBT. White sturgeon at 123-167 dph were less sensitive to copper with LC(50) values ranging from 103.7 to 268.9 μg/L. RBT trout, however, remained more sensitive to copper at 160 dph with an LC(50) value of 30.9 μg/L. The results indicate that high sensitivity to copper in early-life stage white sturgeon may be a factor in recruitment failure occurring in the upper Columbia and Kootenai rivers. When site-specific water-quality criteria were estimated using the biotic ligand model (BLM), derived values were not protective of early-life stage fish, nor were estimates derived by water-hardness adjustment.


Associations of the fecal microbiome with urinary estrogens and estrogen metabolites in postmenopausal women.
The gut microbiota may influence the risk of breast cancer through effects on endogenous estrogens. The objective of the study was to investigate whether urinary estrogens and estrogen metabolites are associated with the diversity and composition of the fecal microbiome. This was a cross-sectional study among women enrolled in Kaiser Permanente of Colorado. A total of 60 women drawn from a random sample of healthy postmenopausal women (aged 55-69 y), without current or recent use of antibiotics or hormone therapy and no history of cancer or gastrointestinal disease participated in the study. OUTCOME MEASURES AND METHODS: Creatinine-standardized urinary estrogens (estrone and estradiol) and 13 hydroxylated estrogen metabolites were measured in spot urines by liquid chromatography-tandem mass spectrometry. The fecal microbiome was assessed using pyrosequencing of 16S rRNA amplicons. General linear models were used to test for associations of diversity and composition of the fecal microbiome with parent estrogen (estrone + estradiol), total estrogens, and estrogen metabolites and the ratio of estrogen metabolites to parent estrogen, which has been predictive of postmenopausal breast cancer risk in previous studies. The ratio of metabolites to parents was directly associated with whole-tree phylogenetic diversity (R = 0.35, P = .01). Relative abundances of the order Clostridiales (R = 0.32, P = .02) and the genus Bacteroides (R = -0.30, P = .03) were also correlated with the ratio of metabolites to parents. Associations were independent of age, body mass index, and study design factors. Our data suggest that women with a more diverse gut microbiome exhibit an elevated urinary ratio of hydroxylated estrogen metabolites to parent estrogen. Further research is warranted to confirm and relate these findings to clinical disease.


Physical Activity, Sedentary Time, and Frailty in Older Migrant Women From Ethnically Diverse Backgrounds: A Mixed-Methods Study.
There is limited evidence examining the association between physical activity (PA), sedentary time (ST), frailty, and factors influencing PA behaviors in migrant older women from ethnically diverse backgrounds. The aims of this mixed-methods study were to: 1) examine PA levels and ST across frailty status; 2) identify any differences in PA/ST between ethnic and religious groups; and 3) qualitatively explore factors influencing PA among older (≥60 years) migrant women (n = 60). PA/ST were assessed using accelerometry and frailty status using the frailty phenotype. Key factors influencing PA were explored via semi-structured interviews (n = 36) and analyzed using thematic analysis. Participants were highly sedentary irrespective of frailty status. Moderate-to-vigorous-physical activity (MVPA) was independently associated with frailty. Participants spent 69% of waking time in ST, with only 15% meeting current weekly PA recommendations. Health-related and socio-cultural factors were reported as common barriers to achieving PA recommendations. Maintaining independence, preventing physical decline and depression were key factors promoting PA. Understanding the challenges and needs of this population can help to inform strategies to promote PA and thus optimize physical function.


CD7+, CD4-, CD8- acute leukemia: a syndrome of malignant pluripotent lymphohematopoietic cells.
Following our initial observation of in vivo conversion of CD7+, CD4-, CD8- acute lymphoblastic leukemia (ALL) cells from lymphoid to myeloid lineages (Proc Natl Acad Sci (USA) 81:253, 1984) we have studied eight additional cases of ALL with this leukemic cell phenotype. The CD7+, CD4-, CD8- phenotype was associated with a distinct clinical entity with those affected predominantly male (either less than 35 years or greater than 65 years of age), with frequent mediastinal and/or thymic masses, skin and CNS disease, high peripheral WBC counts, and bone marrow blasts that were morphologically L1 or not ascribable to a specific lineage. These patients did not respond to conventional chemotherapeutic regimens for either acute lymphoid or myeloid leukemias. No common karyotype or T-cell gene rearrangement pattern could be defined. Importantly, seven of eight patient's leukemic cells studied were capable of multilineage (myeloid, erythroid, monocytoid, megakaryocytoid, and lymphoid) differentiation in vitro. Data is presented suggesting that CD7+, CD4-, CD8- leukemias, in many instances, are leukemias of immature hematopoietic cells. The development of novel therapeutic approaches to this form of leukemia will be necessary to alter its poor prognosis.


Near-infrared emitting CdTe0.5Se0.5/Cd0.5Zn0.5S quantum dots: synthesis and bright luminescence.
We present how CdTe0.5Se0.5 cores can be coated with Cd0.5Zn0.5S shells at relatively low temperature (around 200°C) via facile synthesis using organic ammine ligands. The cores were firstly fabricated via a less toxic procedure using CdO, trioctylphosphine (TOP), Se, Te, and trioctylamine. The cores with small sizes (3.2-3.5 nm) revealed green and yellow photoluminescence (PL) and spherical morphologies. Hydrophobic core/shell CdTe0.5Se0.5/Cd0.5Zn0.5S quantum dots (QDs) with tunable PL between green and near-infrared (a maximum PL peak wavelength of 735 nm) were then created through a facile shell coating procedure using trioctylphosphine selenium with cadmium and zinc acetate. The QDs exhibited high PL efficiencies up to 50% because of the formation of a protective Cd0.5Zn0.5S shell on the CdTe0.5Se0.5 core, even though the PL efficiency of the cores is low (≤1%). Namely, the slow growth process of the shell plays an important role for getting high PL efficiencies. The properties of the QDs are largely determined by the properties of CdTe0.5Se0.5 cores and shells preparation conditions such as reaction temperature and time. The core/shell QDs exhibited a small size diameter. For example, the average diameter of the QDs with a PL peak wavelength of 735 nm is 6.1 nm. Small size and tunable bright PL makes the QDs utilizable as bioprobes because the size of QD-based bioprobes is considered as the major limitation for their broad applications in biological imaging.


Large-area spatially ordered arrays of gold nanoparticles directed by lithographically confined DNA origami.
The development of nanoscale electronic and photonic devices will require a combination of the high throughput of lithographic patterning and the high resolution and chemical precision afforded by self-assembly. However, the incorporation of nanomaterials with dimensions of less than 10 nm into functional devices has been hindered by the disparity between their size and the 100 nm feature sizes that can be routinely generated by lithography. Biomolecules offer a bridge between the two size regimes, with sub-10 nm dimensions, synthetic flexibility and a capability for self-recognition. Here, we report the directed assembly of 5-nm gold particles into large-area, spatially ordered, two-dimensional arrays through the site-selective deposition of mesoscopic DNA origami onto lithographically patterned substrates and the precise binding of gold nanocrystals to each DNA structure. We show organization with registry both within an individual DNA template and between components on neighbouring DNA origami, expanding the generality of this method towards many types of patterns and sizes.