[Opportunities in the home environment for motor development].
To assess the opportunities present in the home environment for motor development of infants. This was a cross-sectional population-based epidemiological study on 239 infants aged three to 18 months who were living in the municipality of Juiz de Fora, Southeastern Brazil, in 2010. The participants were selected by means of stratified random sampling, in clustered multiple stages. To assess the quality and quantity of motor stimulus in the home environment, the "Affordances in the Home Environment for Motor Development - Infant Scale" instrument was used. Bivariate analysis was performed, with application of the chi-square test followed by multinomial logistic regression, in order to investigate associations between the opportunities present in the home and biological, behavioral, demographic and socioeconomic factors. The opportunities for environmental stimulation were relatively low. In the bivariate analysis, for the age group from three to nine months, associations with the following factors were found: birth order (p = 0.06), socioeconomic classification (p = 0.08), monthly income (p = 0.06) and per capita income (p = 0.03). In the regression model, the socioeconomic classification prevailed (OR = 7.46; p = 0.03). For the age group from 10 to 18 months, bivariate analysis showed that the following factors were associated: mother's marital status (p < 0.01), father living with the child (p = 0.08), head of the family (p = 0.04), number of people in the household (p = 0.05), mother's schooling level (p < 0.01), father's schooling level (p < 0.01), socioeconomic classification (p < 0.01) and per capita income (p = 0.03). In the regression model, the mother's marital status (OR = 4.83; p = 0.02), mother's schooling level (OR = 0.29; p = 0.03) and father's schooling level (OR = 0.33; p = 0.04) remained associated with the opportunities for environmental stimulation. Stable partnership between the parents, higher maternal and paternal schooling levels and higher economic level were the factors associated with better opportunities for motor stimulation in the home.


Impact of age on short- and long-term mortality of patients with ST-elevation myocardial infarction in the VIENNA STEMI network.
Our senescent society includes a growing number of elderly people suffering from ST-elevation myocardial infarction (STEMI); however, exactly this population is often underrepresented in randomized trials. Hence, our aim was to investigate the influence of age on patient characteristics, as well as short- and long-term outcome in the Vienna STEMI registry. We included all patients of the Vienna STEMI registry (2003-2009). Patients were stratified into age cohorts (≤45, 46-59, 60-79 and ≥80 years, respectively). Differences between cohorts were investigated by descriptive statistics and regression models. Crude and adjusted mortality rates were investigated using log rank test and Cox regression models, respectively. The influence of treatment on mortality was further investigated using propensity score matching. A total of 4579 patients fulfilled the criteria for further investigation. With rising age of cohorts, the number of females, diabetes mellitus (DM), hypertension (HTN), previous myocardial infarction (MI), shock, no reperfusion therapy and anterior wall infarction significantly increased. In contrast, the number of patients with a positive family history, smoking and hyperlipidemia (HLP) significantly declined. Log rank analysis showed significant differences between age cohorts for short- and long-term mortality. Cox regression analysis for short-term mortality revealed an independent association for age at the event, HTN and shock, while age, smoking, DM, HTN, HLP, previous MI and shock independently influenced long-term mortality after correction for confounders. Also, we found a significant association of age and total ischemic time (TIT), which however had no influence on long-term mortality (interaction term p = 0.236). Propensity score matching revealed reduced mortality rates for patients who received reperfusion therapy compared to conservative management, irrespective of age. Increasing age independently influenced short- and long-term mortality in patients with STEMI in the Vienna STEMI network. The TIT significantly increased with baseline age, but had no impact on mortality. Furthermore, reperfusion therapy exerted beneficial effects irrespective of the patients' age.


Modification of interleukin-15 serum levels in workers exposed to chemotherapeutic agents.
Cytostatic anticancer drugs are known as carcinogenic, mutagenic, and teratogenic risk factors for health care workers occupationally exposed. It has been demonstrated that the administration of interleukin-15 in rat models of colon carcinoma protects against chemotherapy-induced gastrointestinal toxicities. We found that occupational exposure to chemotherapeutic antiblastic agents in vivo modified circulating levels of interleukin-15 in 17 health care workers exposed to antineoplastic drugs in relation to their jobs and in as many healthy age- and sex-matched subjects. Health care workers displayed significantly higher circulating interleukin-15 levels compared to their age-matched controls. If this increase representing an anticancer response remains to be established, these findings strengthen the idea of a therapeutic use of interleukin-15 in the field of cancer.


Hypothermia activates adipose tissue to promote malignant lung cancer progression.
Microenvironment has been increasingly recognized as a critical regulator of cancer progression. In this study, we identified early changes in the microenvironment that contribute to malignant progression. Exposure of human bronchial epithelial cells (BEAS-2B) to methylnitrosourea (MNU) caused a reduction in cell toxicity and an increase in clonogenic capacity when the temperature was lowered from 37°C to 28°C. Hypothermia-incubated adipocyte media promoted proliferation in A549 cells. Although a hypothermic environment could increase urethane-induced tumor counts and Lewis lung cancer (LLC) metastasis in lungs of three breeds of mice, an increase in tumor size could be discerned only in obese mice housed in hypothermia. Similarly, coinjections using differentiated adipocytes and A549 cells promoted tumor development in athymic nude mice when adipocytes were cultured at 28°C. Conversely, fat removal suppressed tumor growth in obese C57BL/6 mice inoculated with LLC cells. Further studies show hypothermia promotes a MNU-induced epithelial-mesenchymal transition (EMT) and protects the tumor cell against immune control by TGF-β1 upregulation. We also found that activated adipocytes trigger tumor cell proliferation by increasing either TNF-α or VEGF levels. These results suggest that hypothermia activates adipocytes to stimulate tumor boost and play critical determinant roles in malignant progression.


Estimating excess 1-year mortality associated with the COVID-19 pandemic according to underlying conditions and age: a population-based cohort study.
The medical, societal, and economic impact of the coronavirus disease 2019 (COVID-19) pandemic has unknown effects on overall population mortality. Previous models of population mortality are based on death over days among infected people, nearly all of whom thus far have underlying conditions. Models have not incorporated information on high-risk conditions or their longer-term baseline (pre-COVID-19) mortality. We estimated the excess number of deaths over 1 year under different COVID-19 incidence scenarios based on varying levels of transmission suppression and differing mortality impacts based on different relative risks for the disease. In this population-based cohort study, we used linked primary and secondary care electronic health records from England (Health Data Research UK-CALIBER). We report prevalence of underlying conditions defined by Public Health England guidelines (from March 16, 2020) in individuals aged 30 years or older registered with a practice between 1997 and 2017, using validated, openly available phenotypes for each condition. We estimated 1-year mortality in each condition, developing simple models (and a tool for calculation) of excess COVID-19-related deaths, assuming relative impact (as relative risks [RRs]) of the COVID-19 pandemic (compared with background mortality) of 1·5, 2·0, and 3·0 at differing infection rate scenarios, including full suppression (0·001%), partial suppression (1%), mitigation (10%), and do nothing (80%). We also developed an online, public, prototype risk calculator for excess death estimation. We included 3 862 012 individuals (1 957 935 [50·7%] women and 1 904 077 [49·3%] men). We estimated that more than 20% of the study population are in the high-risk category, of whom 13·7% were older than 70 years and 6·3% were aged 70 years or younger with at least one underlying condition. 1-year mortality in the high-risk population was estimated to be 4·46% (95% CI 4·41-4·51). Age and underlying conditions combined to influence background risk, varying markedly across conditions. In a full suppression scenario in the UK population, we estimated that there would be two excess deaths (vs baseline deaths) with an RR of 1·5, four with an RR of 2·0, and seven with an RR of 3·0. In a mitigation scenario, we estimated 18 374 excess deaths with an RR of 1·5, 36 749 with an RR of 2·0, and 73 498 with an RR of 3·0. In a do nothing scenario, we estimated 146 996 excess deaths with an RR of 1·5, 293 991 with an RR of 2·0, and 587 982 with an RR of 3·0. We provide policy makers, researchers, and the public a simple model and an online tool for understanding excess mortality over 1 year from the COVID-19 pandemic, based on age, sex, and underlying condition-specific estimates. These results signal the need for sustained stringent suppression measures as well as sustained efforts to target those at highest risk because of underlying conditions with a range of preventive interventions. Countries should assess the overall (direct and indirect) effects of the pandemic on excess mortality. National Institute for Health Research University College London Hospitals Biomedical Research Centre, Health Data Research UK.


Delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses.
The recent development of immunotherapy as a cancer treatment has proved effective over recent years, but the precise dynamics between the tumor microenvironment (TME), nontumor microenvironment (NTME), and the systemic immune system remain elusive. Here, we interrogated these compartments in hepatocellular carcinoma (HCC) using high-dimensional proteomic and transcriptomic analyses. By time-of-flight mass cytometry, we found that the TME was enriched in regulatory T cells (Tregs), tissue resident memory CD8+ T cells (TRMs), resident natural killer cells (NKRs), and tumor-associated macrophages (TAMs). This finding was also validated with immunofluorescence staining on Foxp3+CD4+ and PD-1+CD8+ T cells. Interestingly, Tregs and TRMs isolated from the TME expressed multiple markers for T-cell exhaustion, including PD-1, Lag-3, and Tim-3 compared with Tregs and TRMs isolated from the NTME. We found PD-1+ TRMs were the predominant T-cell subset responsive to anti-PD-1 treatment and significantly reduced in number with increasing HCC tumor progression. Furthermore, T-bet was identified as a key transcription factor, negatively correlated with PD-1 expression on memory CD8+ T cells, and the PD-1:T-bet ratio increased upon exposure to tumor antigens. Finally, transcriptomic analysis of tumor and adjacent nontumor tissues identified a chemotactic gradient for recruitment of TAMs and NKRs via CXCR3/CXCL10 and CCR6/CCL20 pathways, respectively. Taken together, these data confirm the existence of an immunosuppressive gradient across the TME, NTME, and peripheral blood in primary HCC that manipulates the activation status of tumor-infiltrating leukocytes and renders them immunocompromised against tumor cells. By understanding the immunologic composition of this gradient, more effective immunotherapeutics for HCC may be designed.


NHS reference costs: a history and cautionary note.
Historically, the NHS did not routinely collect cost data, unlike many countries with private insurance markets. In 1998, for the first time the government mandated NHS trusts to submit estimates of their costs of service, known as reference costs. These have informed a wide range of health economic evaluations and important functions in the health service, such as setting prices.Reference costs are collected by progressively disaggregating budgets top-down into disease and treatment groups. Despite ongoing improvements to methods and guidance, these submissions continued to suffer a lack of accuracy and comparability, fundamentally undermining their credibility for critical functions.To overcome these issues, there was a long-held ambition to collect "patient-level" cost data. Patient-level costs are estimated with a combination of disaggregating budgets but also capturing the patient-level "causality of costs" bottom-up in the allocation of resources to patient episodes. These not only aim to capture more of the drivers of costs, but also improve consistency of reporting between providers.The change in methods may confer improvements to data quality, though judgement is still required and achieving consistency between trusts will take further work. Estimated costs may also change in important ways that may take many years to fully understand. We end on a cautionary note that patient-level cost methods may unlock potential, they alone contribute little to our understanding of the complexities involved with service quality or need, while that potential will require substantial investment to realise. Many healthcare resources cannot be attributed to individual patients so the very notion of "patient-level" costs may be misplaced. High hopes have been put in these new data, though much more work is now necessary to understand their quality, what they show and how their use will impact the system.


Efficacy and outcome of molecular targeted therapies in elderly patients with hepatocellular carcinoma: Relative dose intensity associated with overall survival.
Indications of drug therapies to elderly patients with hepatocellular carcinoma (HCC) should be carefully determined. The current study assessed the safety and efficacy of molecular targeted agents (MTAs) in the elderly patients with HCC, and identified factors associated with prognosis in a real-world clinical setting. In a retrospective observational study, clinical data of patients with unresectable HCC treated with sorafenib or lenvatinib as first-line treatment at our hospital between 2011 and 2022, were investigated. Clinical parameters, therapeutic effects, adverse events (AEs), and prognosis were evaluated separately for the non-elderly (<75 years old) and elderly patients (≥75 years old). Overall, 111 patients were enrolled, including 59 non-elderly and 52 elderly patients. Compared to the non-elderly patients, the elderly patients had significantly lower skeletal muscle mass and a significantly lower percentage of patients in poor general condition with performance status 2 or higher, but there were no differences in parameters related to liver function or nutritional status. There were no significant differences in the incidence of severe AEs and therapeutic effects between the groups. No significant difference in progression-free survival was observed in the elderly and non-elderly patients; however, overall survival (OS) for sorafenib treatment was shorter in the elderly patients than in the non-elderly patients. Elderly patients consumed lower doses of both the drugs, and relative dose intensity (RDI) 4 weeks after treatment (4W-RDI) was associated with OS. Further, OS in the elderly patients was significantly longer in the subgroup with high 4W-RDI as compared to that in the subgroup with low 4W-RDI. MTAs can be safely administered to elderly patients with HCC. Furthermore, 4W-RDI is associated with longer OS. Maintaining RDI in the early phase is crucial in predicting the success of treatment with MTAs, especially in the elderly patients.


Terminology in morphological anomalies of the cerebellum does matter.
Neuroimaging plays a key role in the diagnostic work-up of morphological abnormalities of the cerebellum. Diagnostic criteria for numerous morphological anomalies of the cerebellum are based on neuroimaging findings. Various morphological patterns have been described on neuroimaging including cerebellar hypoplasia, cerebellar agenesis, pontocerebellar hypoplasia, cerebellar dysplasia, cerebellar dysmorphia, and cerebellar atrophy. These patterns have specific differential diagnoses. The familiarity with the diagnostic criteria is mandatory for a correct diagnosis and a targeted work-up to avoid unnecessary investigations. A correct diagnosis is essential for early therapy, prognosis, and counseling of the affected children and their family.


Daily variation in ethnic identity, ethnic behaviors, and psychological well-being among American adolescents of Chinese descent.
This study examined the links among Chinese American adolescents' (N = 96) global ethnic identity and their ethnic behaviors, ethnic identity salience, and psychological well-being based on daily diaries collected over a 2-week period. The daily association between engagement in ethnic behaviors and ethnic salience was positive regardless of overall ethnic identity. The daily-level association between ethnic identity salience and well-being, however, was dependent on adolescents' global ethnic identity. Among adolescents who were moderate or high in global ethnic identity, ethnic identity salience was consistently associated with positive well-being at the daily level. In contrast, the daily association between ethnic identity salience and well-being was less strong for youths who were low in ethnic identity. Additionally, a higher level of salience and a weaker association between salience and negative symptoms was found for girls than for boys, and older youths reported a weaker association between salience and positive symptoms than did younger youths.


Physician understanding and application of surrogate decision-making laws in clinical practice.
Although state surrogate laws are the most common way surrogate decision makers are identified, no studies have been conducted to determine physician understanding of these laws or how these laws are utilized during clinical practice. The purpose of this study is to better understand how surrogate decision-making laws function in practice. A cross-sectional survey of 412 physicians working in Indiana hospitals was conducted between November 2014 and January 2015 to determine physicians' knowledge of Indiana's surrogate decision-making law and physicians' approaches to hypothetical cases using the law in clinical practice. Fewer than half of physicians (48%) were able to correctly identify all legally allowable surrogate decision makers. Of those physicians who knew the law, nearly all of them (98%) indicated that they would violate the law during clinical practice by allowing nonlegal surrogates such as grandchildren to make medical decisions. A majority of physicians endorse relying on surrogates who have strong ties to the patient but are not legally allowable in Indiana. It is possible that these decisions reflect sound ethical reasoning even though they are illegal. Due to the narrow construction of some state surrogate decision laws, physicians may be placed in the position where they must either choose to follow medical ethical principles or the law. To alleviate these issues, state surrogate decision laws need to be amended to include a broader list of surrogates, such as extended family and close friends.


Cancer-associated stromal fibroblasts promote pancreatic tumor progression.
Pancreatic adenocarcinoma is characterized by a dense background of tumor associated stroma originating from abundant pancreatic stellate cells. The aim of this study was to determine the effect of human pancreatic stellate cells (HPSC) on pancreatic tumor progression. HPSCs were isolated from resected pancreatic adenocarcinoma samples and immortalized with telomerase and SV40 large T antigen. Effects of HPSC conditioned medium (HPSC-CM) on in vitro proliferation, migration, invasion, soft-agar colony formation, and survival in the presence of gemcitabine or radiation therapy were measured in two pancreatic cancer cell lines. The effects of HPSCs on tumors were examined in an orthotopic murine model of pancreatic cancer by co-injecting them with cancer cells and analyzing growth and metastasis. HPSC-CM dose-dependently increased BxPC3 and Panc1 tumor cell proliferation, migration, invasion, and colony formation. Furthermore, gemcitabine and radiation therapy were less effective in tumor cells treated with HPSC-CM. HPSC-CM activated the mitogen-activated protein kinase and Akt pathways in tumor cells. Co-injection of tumor cells with HPSCs in an orthotopic model resulted in increased primary tumor incidence, size, and metastasis, which corresponded with the proportion of HPSCs. HPSCs produce soluble factors that stimulate signaling pathways related to proliferation and survival of pancreatic cancer cells, and the presence of HPSCs in tumors increases the growth and metastasis of these cells. These data indicate that stellate cells have an important role in supporting and promoting pancreatic cancer. Identification of HPSC-derived factors may lead to novel stroma-targeted therapies for pancreatic cancer.


Concomitant loss of NDH complex-related genes within chloroplast and nuclear genomes in some orchids.
The chloroplast NAD(P)H dehydrogenase-like (NDH) complex consists of about 30 subunits from both the nuclear and chloroplast genomes and is ubiquitous across most land plants. In some orchids, such as Phalaenopsis equestris, Dendrobium officinale and Dendrobium catenatum, most of the 11 chloroplast genome-encoded ndh genes (cp-ndh) have been lost. Here we investigated whether functional cp-ndh genes have been completely lost in these orchids or whether they have been transferred and retained in the nuclear genome. Further, we assessed whether both cp-ndh genes and nucleus-encoded NDH-related genes can be lost, resulting in the absence of the NDH complex. Comparative analyses of the genome of Apostasia odorata, an orchid species with a complete complement of cp-ndh genes which represents the sister lineage to all other orchids, and three published orchid genome sequences for P. equestris, D. officinale and D. catenatum, which are all missing cp-ndh genes, indicated that copies of cp-ndh genes are not present in any of these four nuclear genomes. This observation suggests that the NDH complex is not necessary for some plants. Comparative genomic/transcriptomic analyses of currently available plastid genome sequences and nuclear transcriptome data showed that 47 out of 660 photoautotrophic plants and all the heterotrophic plants are missing plastid-encoded cp-ndh genes and exhibit no evidence for maintenance of a functional NDH complex. Our data indicate that the NDH complex can be lost in photoautotrophic plant species. Further, the loss of the NDH complex may increase the probability of transition from a photoautotrophic to a heterotrophic life history.


Catecholamine synthesis is mediated by tyrosinase in the absence of tyrosine hydroxylase.
Catecholamine neurotransmitters are synthesized by hydroxylation of tyrosine to L-dihydroxyphenylalanine (L-Dopa) by tyrosine hydroxylase (TH). The elimination of TH in both pigmented and albino mice described here, like pigmented TH-null mice reported previously (Kobayashi et al., 1995; Zhou et al., 1995), demonstrates the unequivocal requirement for catecholamines during embryonic development. Although the lack of TH is fatal, TH-null embryos can be rescued by administration of catecholamine precursors to pregnant dams. Once born, TH-null pups can survive without further treatment until weaning. Given the relatively rapid half-life of catecholamines, we expected to find none in postnatal TH-null pups. Despite the fact that the TH-null pups lack TH and have not been supplemented with catecholamine precursers, catecholamines are readily detected in our pigmented line of TH-null mice by glyoxylic acid-induced histofluorescence at postnatal day 7 (P7) and P15 and quantitatively at P15 in sympathetically innervated peripheral organs, in sympathetic ganglia, in adrenal glands, and in brains. Between 2 and 22% of wild-type catecholamine concentrations are found in these tissues in mutant pigmented mice. To ascertain the source of the catecholamine, we examined postnatal TH-null albino mice that lack tyrosinase, another enzyme that converts tyrosine to L-Dopa but does so during melanin synthesis. In contrast to the pigmented TH-null mice, catecholamine histofluorescence is undetectable in postnatal albino mutants, and the catecholamine content of TH-null pups lacking tyrosinase is 18% or less than that of TH-null mice with tyrosinase. Thus, these extraordinary circumstances reveal that tyrosinase serves as an alternative pathway to supply catecholamines.


Racial Differences in Misclassification of Healthy Eating Based on Food Frequency Questionnaire and 24-Hour Dietary Recalls.
To examine the agreement in nutrient intake and alternate healthy eating indices (AHEI) between a self-administered Food Frequency Questionnaire (FFQ) and 24-hour recall (24HR) measurements of diet by race, among urban older women. Cross-sectional observational study. Urban neighborhoods in Washington, DC, USA. Community-dwelling White and Black women aged 65 and older. In 2014 and 2015, 49 White and 44 Black older women were queried on diet using both FFQ and 24-hour recalls. The correlation coefficients of 55 nutrient intake measures and agreements on healthy eating classification between the two instruments were compared overall and by race. The mean correlation coefficient (rho) was 0.46 for Whites and 0.23 for Blacks. For 47 measures, rho was lower for Blacks. Whites had a strong correlation of ≥0.5 for 28 items, while Blacks had strong correlations for only 3 items. Based on FFQ, the mean (SD) of AHEI were 54.0 (10.3) for Whites and 45.9 (8.8) for Blacks (p<0.001). Based on 24HR, the mean (SD) were 43.9 (10.8) for Whites and 33.2 (9.6) for Blacks (p<0.001). Using 32 as the cutoff (40% of maximum AHEI score), 50% of Blacks and 14% of Whites were classified as eating unhealthy based on the 24HR, versus 2.6% and 0% based on the FFQ. The FFQ has limited ability to accurately assess nutrient intake among older Black women, and tends to underestimate racial differences in healthy eating. The FFQ should be further improved for use in racial disparities research of healthy eating in older age, using a larger sample of older women with racial and geographic diversities.


Conceptual and methodologic challenges of assessing the short-term efficacy of Guggulu in obesity: data emergent from a naturalistic clinical trial.
An open comparative trial was conducted in 58 adult obese patients (Body Mass Index > or = 25 kg/square metre). Group I (n = 27), non-drug, was advised diet (1200-1600 cals) and a brisk walk for 30 minutes. Group II, in addition, received Guggulu (Medohar) 1.5-3 gms/day for 30 days. Mean difference in weight loss between Guggulu and non-drug group was 0.32 kg (ns) on day 15 and 0.58 kg on day 30 (ns). The mean weight reduction in patients (> 90 kgs) was 1.92 kg (ns) and 2.25 kg (ns) higher in Guggulu group. All patients weighing > 90 kg lost weight in Guggulu group whilst 3 in non-drug group did not lose weight. Guggulu was tolerated well. The data from this pilot study suggest a synergistic diet-Guggulu interaction over 30 days in patients weighing > 90 kgs which needs to be confirmed in a large placebo controlled study.


Self-reported differences on measures of executive function and hypersexual behavior in a patient and community sample of men.
Patients seeking help for hypersexual behavior often exhibit features of impulsivity, cognitive rigidity, poor judgment, deficits in emotion regulation, and excessive preoccupation with sex. Some of these characteristics are also common among patients presenting with neurological pathology associated with executive dysfunction. These observations led to the current investigation of differences between a group of hypersexual patients (n = 87) and a non-hypersexual community sample (n = 92) of men using the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) and the Hypersexual Behavior Inventory (HBI). Significant differences between the groups emerged on eight subscales and all of the general indices of executive functioning with the most dramatic differences on BRIEF-A's Shift, Emotional Control, Initiate, and Plan/Organize subscales. Hypersexual behavior was positively correlated (r = .37, p < .01) with global indices of executive dysfunction and several subscales of the BRIEF-A. These findings provide preliminary evidence supporting the hypothesis that executive dysfunction may be implicated in hypersexual behavior.


Recognition of disparate HA and NS1 peptides by an H-2Kd-restricted, influenza specific CTL clone.
CTLs (CD8+) are known to recognize exogenous peptide in the context of class I MHC molecules. We observed that an influenza subtype H1 and H2 cross-reactive CTL clone B7, which was stimulated by a fusion protein containing a portion of HA2 subunit of A/PR/8 virus HA, recognized a synthetic peptide (residues 515-526) of the HA2 subunit of A/PR/8 virus strain. This CTL clone also recognized a structurally disparate NS1 peptide 50-68 of the same A/PR/8 virus. We examined the recognition of the NS1 peptide 50-68 and the HA peptide 515-526 by the subcloned CTL clone, B7-B7. Cold target inhibition experiments showed that the recognition of the HA peptide by the CTL clone B7-B7 could be competed by NS1 peptide-treated target cells and vice versa. The recognition of both NS1 peptide and HA peptide by the CTL clone B7-B7 was restricted by the same allele, H2Kd. In addition, this NS1 peptide requires approximately a 600-fold higher concn for optimal CTL recognition than did the HA peptide. We conclude that the TCR on clone B7-B7 recognizes the HA peptide or the NS1 peptide as comparable complexes with the same class I MHC molecules, although there is no obvious homology in the primary sequences of HA 515-526 and NS1 50-68 peptides. CTLs elicited with certain antigens appear to recognize distinctively different antigens complexed to the same presenting MHC molecule.


Antagonist properties of polyamines and bis(ethyl)polyamines at N-methyl-D-aspartate receptors.
The polyamine spermine has both stimulatory and inhibitory effects on N-methyl-D-aspartate (NMDA) receptors. At recombinant NMDA receptors, effects of spermine are dependent on the subunit composition of the receptor. In the present work we have used voltage-clamp recording to examine the effects of polyamines and bis(ethyl)polyamines on recombinant NMDA receptors expressed in Xenopus oocytes. The compounds that were studied include several bis(ethyl)polyamines that may be clinically useful as antitumor agents. A number of pentaamines and bis(ethyl)pentaamines were found to act as potent voltage-dependent antagonists at heteromeric NR1A/NR2A and NR1A/NR2B receptors, but not at NR1A/NR2C receptors. Antagonism was more pronounced in oocytes voltage-clamped at -80 mV than at -20 mV. Some polyamine analogs also potentiated responses to glutamate at NR1A/NR2B receptors at membrane potentials of -20 to +40 mV, but this effect required higher concentrations of polyamines than did inhibition seen at hyperpolarized membrane potentials. At NR1A/NR2A receptors the block seen with pentaamines and bis(ethyl)pentaamines, but not with spermine or bis(ethyl)spermine, was maximal at a membrane potential of -100 mV and was relieved at more negative as well as at more positive membrane potentials. This suggests that the mechanism of inhibition of NMDA receptors by pentaamines is different from that of spermine. Pentaamines may permeate the ion channel of NMDA receptors at very hyperpolarized membrane potentials and may be useful for studying the structural properties of NMDA receptor channels.


Identification of Burkholderia cepacia isolates from patients with cystic fibrosis and use of a simple new selective medium.
We evaluated 819 isolates referred to us as "Burkholderia cepacia" from cystic fibrosis (CF) clinics and research laboratories from five countries; 28 (3.4%) were not B. cepacia. A further 12 (1.5%) organisms appeared to be other Burkholderia species, but identification could not be confirmed by conventional means. The most prevalently misidentified organisms were Stenotrophomonas maltophilia, Alcaligenes xylosoxidans, and Comamonas acidovorans. Many of these organisms grew on oxidation-fermentation polymyxin-bacitracin-lactose (OFPBL) and Pseudomonas cepacia agars, selective media currently used for B. cepacia isolation. We developed a new medium, B. cepacia selective agar (BCSA), which is more enriched for the growth of B. cepacia yet which is more selective against other organisms than currently available selective agars. A total of 190 of 191 (99.5%) isolates of B. cepacia from patients with CF grew on BCSA without vancomycin, whereas 100% grew on OFPBL agar and 179 (94.2%) grew on P. cepacia agar. Of 189 other gram-negative and gram-positive organisms tested, 10 (5.3%) grew on BCSA without vancomycin. The addition of vancomycin to BCSA lowered the false positivity rate to 3.7% without further inhibition of B. cepacia. The false positivity rates for OFPBL and P. cepacia agars were 19.6 and 13.8%, respectively. Isolates of B. cepacia from CF patients grew most quickly on BCSA, with 201 of 205 (98.0%) being readily visible within 24 h, whereas 182 (88.8%) grew on OFPBL agar and 162 (79.0%) grew on P. cepacia agar within 24 h. We propose that the use of BCSA will allow investigators to overcome many of the difficulties associated with the identification of B. cepacia and should be considered for use as a primary isolation agar for specimens from patients with CF.


A novel monodisperse SiO2@C-dot for the rapid and facile identification of latent fingermarks using self-quenching resistant solid-state fluorescence.
Solid powder fluorescence shows great potential for application in medicine, biology, and engineering, especially in the identification of latent fingermarks in forensic science. However, conventional developing methods suffer from some drawbacks, such as low contrast, low sensitivity, low selectivity, and high toxicity. To conquer these challenges, novel SiO2@C-dot microspheres were prepared via a facile one-pot hydrothermal method by using citric acid as a carbon source and aminosilane as a nitrogen source. Interestingly, the results showed that the resultant powders possess good monodispersity, high fluorescence emission, and resistance to self-quenching. Additionally, the mechanism for the solid-state fluorescence of SiO2@C-dot compounds was also investigated. More importantly, the fingermarks on various surfaces, including transparent glasses, ceramic tiles, transparent plastics, aluminum alloys, plastic cards, painted woods, artificial leathers, and Chinese paper money, developed by the powders have indicated well-defined papillary ridges under a 365 nm UV lamp. The novel strategy of using monodisperse SiO2@C-dot microspheres as a fluorescent label for developing latent fingermarks showed greater advantages compared to conventional methods, which was also demonstrated using the automatic fingerprint identification system. It is simple, rapid, low-cost, nontoxic, and effective, and is expected to be a promising alternative for the development of latent fingerprints in forensic science.


WOLBACHIA AND THE EVOLUTION OF REPRODUCTIVE ISOLATION BETWEEN DROSOPHILA RECENS AND DROSOPHILA SUBQUINARIA.
Endosymbiotic bacteria of the genus Wolbachia are widespread among insects and in many cases cause cytoplasmic incompatibility in crosses between infected males and uninfected females. Such findings have been used to argue that Wolbachia have played an important role in insect speciation. Theoretical models, however, indicate that Wolbachia alone are unlikely to lead to stable reproductive isolation between two formerly conspecific populations. Here we analyze the components of reproductive isolation between Drosophila recens, which is infected with Wolbachia, and its uninfected sister species Drosophila subquinaria. Laboratory pairings demonstrated that gene flow via matings between D. recens females and D. subquinaria males is hindered by behavioral isolation. Matings readily occurred in the reciprocal cross (D. quinaria females × D. recens males), but very few viable progeny were produced. The production of viable hybrids via this route was restored by antibiotic curing of D. recens of their Wolbachia symbionts, indicating that hybrid offspring production is greatly reduced by cytoplasmic incompatibility in the crosses involving infected D. recens males. Thus, behavioral isolation and Wolbachia-induced cytoplasmic incompatibility act as complementary asymmetrical isolating mechanisms between these two species. In accordance with Haldane's rule, hybrid females were fertile, whereas hybrid males invariably were sterile. Levels of mtDNA variation in D. recens are much lower than in either D. subquinaria or D. falleni, neither of which is infected with Wolbachia. The low haplotype diversity in D. recens is likely due to an mtDNA sweep associated with the spread of Wolbachia. Nevertheless, the existence of several mtDNA haplotypes in this species indicates that Wolbachia have been present as a potential isolating mechanism for a substantial period of evolutionary time. Finally, we argue that although Wolbachia by themselves are unlikely to bring about speciation, they can increase the rate of speciation in insects.


Sentinel lymph node biopsy in elderly irish patients with malignant melanoma.
In patients with malignant melanoma, Breslow depth increases with age. However, studies suggest that the frequency of sentinel lymph node metastases in malignant melanoma decreases with age. We investigated whether this applied to the cohort of patients undergoing sentinel lymph node biopsy (SLNB) in our institution. In a prospectively accrued database we identified 149 patients undergoing SLNB from 1997 to 2005. Tumour thickness as measured by Breslow depth was assessed in stratified age groups. We assessed the relationship between SLNB positivity and age using the Chi-square for trend. We directly examined the relationship between SLNB positivity in patients aged less than 65 and aged 65 years of age and over. Disease-free and overall survival in patients aged less than 65 and aged 65 years of age and over were also assessed. Comparing the age groups, there was no significant difference identified in Breslow depth (<65 years, median Breslow > or = 1.2 mm (range 0.2-9.7); > or =65 years, median Breslow > or = 1.4 mm (range 0.12-8.5); p > or = 0.06, Mann-Whitney U). Chi-square for trend identified no significant relationship between SLNB positivity and age. We found n=120 patients <65 had SLNB, of which 26 (21.7%) were positive. In patients =65, n=29 had SLNB of which 3 (10.3%) were positive. These differences were not statistically significant (Fisher's exact test, p > or = 0.2). There was no difference in disease-free or overall survival between patients aged <65 or > or =65 who had SLNB (median follow-up 37.5 months (range 5-70); disease-free survival, p > 0.08; overall survival, p > or = 0.3, Logrank test). We did not find that elderly patients with malignant melanoma had a demonstrable difference in tumour thickness when compared to younger patients. In those patients who underwent SLNB there was no significant difference in node positivity between the age groups. Disease-free and overall survival were not significantly different between the age groups. Further study and longer follow-up will help establish the relationship between age and SLNB positivity.


Delivery of screening and brief intervention for unhealthy alcohol use in an urban academic Federally Qualified Health Center.
Screening and brief intervention (SBI) for unhealthy drinking has not been widely implemented in primary care partly due to reliance on physicians to perform it. We implemented a model of nursing staff-delivered SBI for unhealthy drinking for adult patients receiving primary care at an academically-affiliated Federally Qualified Health Center in the Bronx, NY. Our model consisted of nursing staff screening all patients with the alcohol use disorders identification test consumption questions (AUDIT-C) and, if screening positive, providing BI or referral to specialty services. We developed a clinical decision support tool integrated into the electronic health record to guide nursing staff and record SBI provision. To evaluate this model, we determined overall SBI delivery to patients and factors associated with receiving SBI. Between October 2013 and September 2014, 9119 unique adult patients made 24,285 visits. Patients were majority women (67.5%) and Hispanic/Latino (54.5%). Overall, 46.2% were screened, with 19.0-35.8% of eligible patients screened in each month. Increasing age (OR: 0.82 [95% CI 0.80-0.85] for a 10-year increase), female sex (OR: 0.83 [95% CI 0.77-0.91]), and chronic conditions like hypertension (OR: 0.62 [95% CI 0.56-0.70]) and diabetes (OR: 0.66 [95% CI 0.58-0.75]), among others, were associated with a lower odds of being screened. Of all patients screened, 225 (5.3%) screened positive and of those patients, 122 (54.2%) received a BI. Patients with higher AUDIT-C scores were more likely to receive a BI (OR: 1.24 [95% CI 1.04-1.47] for a 1-point increase) and non-English speaking patients were less likely to receive a BI than those who spoke English (OR: 0.42 [95% CI 0.18-0.97]). Our model of SBI resulted in screening of nearly half of all eligible patients and BI provision to over half of those screening positive. Future efforts to improve SBI delivery should focus on groups such as older adults, women, and those with chronic medical conditions.


Generation of a multipathogen-specific T-cell product for adoptive immunotherapy based on activation-dependent expression of CD154.
Viral and fungal infections remain a leading cause of mortality in patients after hematopoietic stem cell transplantation (HSCT). Adoptive transfer of multipathogen-specific T cells is promising in restoring immunity and thereby preventing and treating infections, but approaches are currently limited because of time-consuming and laborious procedures. Therefore, we investigated a new strategy to simultaneously select T cells specific for viral and fungal pathogens based on activation-dependent expression of CD154. Single- and multipathogen-specific T-cell lines with high specificity for adenovirus (AdV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), Candida albicans, and/or Aspergillus fumigatus could be readily generated within 14 days irrespective of the precursor frequency. The T-cell lines responded reproducibly to endogenously processed antigen and specifically proliferated upon antigenic stimulation. Although isolation based on CD154 favors enrichment of CD4(+) T cells, AdV-, EBV- and CMV-specific CD8(+) T cells could be expanded and demonstrated lysis of target cells. Conversely, T cell-mediated alloreactivity was almost abrogated compared with the starting fraction. This selection and/or expansion strategy may form the basis for future adoptive immunotherapy trials in patients at risk for multiple infections and may be translated to other antigens.


Assessment of Grating Acuity in Infants and Toddlers Using an Electronic Acuity Card: The Dobson Card.
To determine if testing binocular visual acuity in infants and toddlers using the Acuity Card Procedure (ACP) with electronic grating stimuli yields clinically useful data. Participants were infants and toddlers ages 5 to 36.7 months referred by pediatricians due to failed automated vision screening. The ACP was used to test binocular grating acuity. Stimuli were presented on the Dobson Card. The Dobson Card consists of a handheld matte-black plexiglass frame with two flush-mounted tablet computers and is similar in size and form to commercially available printed grating acuity testing stimuli (Teller Acuity Cards II [TACII]; Stereo Optical, Inc., Chicago, IL). On each trial, one tablet displayed a square-wave grating and the other displayed a luminance-matched uniform gray patch. Stimuli were roughly equivalent to the stimuli available in the printed TACII stimuli. After acuity testing, each child received a cycloplegic eye examination. Based on cycloplegic retinoscopy, patients were categorized as having high or low refractive error per American Association for Pediatric Ophthalmology and Strabismus vision screening referral criteria. Mean acuities for high and low refractive error groups were compared using analysis of covariance, controlling for age. Mean visual acuity was significantly poorer in children with high refractive error than in those with low refractive error (P = .015). Electronic stimuli presented using the ACP can yield clinically useful measurements of grating acuity in infants and toddlers. Further research is needed to determine the optimal conditions and procedures for obtaining accurate and clinically useful automated measurements of visual acuity in infants and toddlers.


Evaluation and benchmarking of a pixel-shifting camera for superresolution lensless digital holography.
In lensless digital holography, the comparatively low resolution of the CCD devices that are used to record the digital holograms has to date limited both the maximum linear dimensions of the measurement object and also the minimum possible stand-off distance between the object and the CCD detector. A signal-processing-based technique known as superresolution (SR) image reconstruction can provide an alternative approach that reduces these restrictions. We report on an SR image reconstruction technique that has been introduced by employing a camera with a "microscanning" function to capture SR digital holograms via multiple subpixel movements of the CCD sensor. A detailed description of the approach is given, along with experimental results, which are discussed and evaluated, showing the advantages of using this method. An approach using three-dimensional holographic contouring is also described that may be adopted as a strategy for benchmarking newly developed algorithms at any stage of the lensless digital holographic process.


Towards integrated nanoplasmonic logic circuitry.
Surface plasmon polaritons (SPPs) may serve as ultimate data processing expedients in future nanophotonic applications. SPPs combine the high localization of electrons with the bandwidth, frequency and propagation properties of photons, thus supplying nature with the best of two worlds. However, although plasmonics have recently gained constantly growing scientific attention, logic devices that operate on SPPs on a deep nanometer scale are yet to be demonstrated. Here, we design, fabricate and experimentally verify the smallest, first ever reported all optical nanoplasmonic XOR logic gate. The introduced XOR device is based on a novel engineerable interferometry scheme with extremely compact dimensions of λ(3)/15,500, which can be used to realize a variety of plasmonic logic functionalities. We use frequency modulated Kelvin probe microscopy to provide evidence of binary XOR functionality performed directly on SPPs with λ(3)/80,000 mode volumes. An extinction ratio of 10 dB is achieved for a device length of 150 nm, increasing up to 30 dB for a device length of 280 nm. Our findings confirm plasmonics as the favorite data carriers in integrated all optical logic devices operating on the deep nanoscale, and pave the way to the development of future ultrafast information processing technologies based on SPPs.


3D aligned-carbon-nanotubes@Li2FeSiO4 arrays as high rate capability cathodes for Li-ion batteries.
3D aligned-carbon-nanotubes (ACNTs)@Li2FeSiO4 nanocomposite arrays on Al foil were developed as cathode materials for Li-ion batteries. The ACNTs were grown directly on an Al foil by a chemical vapor deposition method to achieve a 3D current collector structure for direct charge transport. Li2FeSiO4 nanoparticles were deposited on the surface of the ACNTs by a polyvinylalcohol (PVA)-assisted sol-gel method. The 3D samples showed a high degree of alignment of nanotubes with a favorable pore morphology before and after cycling. According to electrochemical measurements, the 3D sample with optimized mass ratio of ACNTs and Li2FeSiO4 (2:1) showed excellent rate capability and capacity retention, delivering a discharge specific capacity of 142 mAh g(-1) at a rate of 0.5 C (C = 160 mAg(-1)) and maintaining 99% of the initial discharge capacity after 50 cycles at 24 ° C. Up to 20 C, the delivered charge/discharge capacity was 94 mAh g(-1) after 172 cycles, which is 54% of the value obtained at C/20 (175 mAh g(-1)). In comparison, carbon coated nanoporous Li2FeSiO4 obtained under analogous conditions by a PVA-assisted sol-gel method can only deliver a capacity of 80 mAh g(-1) and showed poor rate capability. In addition, despite amorphization, dissolution and chemical composition changes occurring in the 3D samples upon extended cycling, the 3D samples showed good long-term cycling stability at a high current density (5 C), maintaining ~80% of the initial discharge capacity after 1000 cycles and ~70% after 2000 cycles.


Three-dimensional observation of internal defects in semiconductor crystals by use of two-photon excitation.
We present a method of three-dimensional observation of internal defects in semiconductor crystals for blue lasers by use of two-photon excitation. We excite photoluminescence by using a two-photon process. Since semiconductor materials have intrinsically high absorption in the short-wavelength region, the excitation light of photoluminescence is largely absorbed by the crystals. It is difficult to observe defects in deep regions. Two-photon excitation can overcome this limitation because near-infrared light can be used instead of blue light for excitation of photoluminescence, and the near-infrared light is absorbed at only the focused point. The excitation light can penetrate into the deep regions of the crystal. We succeeded in observing defects in a ZnSe crystal ~200 microm below the crystal surface. This is, as far as we know, the first demonstration of the observation of three-dimensional structures of defects in semiconductor crystals by the use of two-photon excitation.


Diminished effect of maternal age on implantation after preimplantation genetic diagnosis with array comparative genomic hybridization.
To assess the relationship between maternal age, chromosome abnormality, implantation, and pregnancy loss. Multicenter retrospective study. IVF centers in the United States. IVF patients undergoing chromosome screening. Embryo biopsy on day 3 or day 5/6 with preimplantation genetic diagnosis (PGD) by array comparative genomic hybridization. Aneuploidy, implantation, pregnancy, and loss rates. Aneuploidy rates increased with maternal age from 53% to 93% for day 3 biopsies and from 32% to 85% for blastocyst biopsies. Implantation rates for euploid embryos for ages <35-42 years did not decrease after PGD: ranges 44%-32% for day 3 and 51%-40% for blastocyst. Ongoing pregnancy rates per transfer did not decrease for maternal ages <42 years after PGD with day 3 biopsy (48.5%-38.1%) or blastocyst biopsy (64.4%-54.5%). Patients >42 years old had implantation rates of 23.3% (day 3), 27.7% (day 5/6), and the pregnancy rate with day 3 biopsy was 9.3% and with day 5 biopsy 10.3%. Selective transfer of euploid embryos showed that implantation and pregnancy rates were not significantly different between reproductively younger and older patients up to age 42 years. Some patients who start an IVF cycle planning to have chromosome screening do not have euploid embryos available for transfer, a situation that increases with advancing maternal age. Mounting data suggests that the dramatic decline in IVF treatment success rates with female age is primarily caused by aneuploidy.


Differences of the midline-crossing venous drainage pattern in supraumbilical and infraumbilical regions: Angiographic study using fresh cadavers.
Current clinical and anatomical studies show that the venous problem associated with the deep inferior epigastric perforator flap results from poor midline-crossing. We examined the venous anatomy of the infraumbilical midline area and the dynamic venous flow of the deep inferior epigastric perforator flap in nine fresh cadavers. All nine abdominal specimens were harvested between the subcostal margin and the groin crease. Two specimens were used to analyze the abdominal venous anatomy, one of which was divided into two hemi-abdominal specimens. The remaining seven specimens were harvested as deep inferior epigastric perforator flaps with one major paraumbilical perforator. Venous cannulation and serial angiographic agent injection were performed in several conditions. Each specimen was radiographed using a soft X-ray system. For additional information, computed tomography (CT) angiography-visualized superficial inferior epigastric veins (SIEVs) and the supraumbilical branch were analyzed. We noted that the venous drainage between the bilateral SIEVs was easier to configure in the supraumbilical area than in the infraumbilical area. Only one to two short polygonal venous networks connect the bilateral superficial inferior epigastric veins in the supraumbilical area; however, long and multiple polygonal venous networks connect the bilateral superficial inferior epigastric veins in the infraumbilical area, which could be a predisposing factor for venous congestion. The mean distance from the umbilicus upper border to evident supraumbilical midline crossover was 18.39±4.03 mm (range: 10.10-28.49) in CT angiograms. In cadaver specimens, the mean distance was 10.87±4.85 mm (range: 4.6-18.9). Supraumbilical midline crossover was more favorable than infraumbilical midline crossover in venous flow.


Marrow stromal stem cells.
Evidence for the hypothesis that there are stromal stem cells present in the soft connective tissues associated with marrow and bone surfaces that are able to give rise to a number of different cell lines is reviewed. The lines are currently designated fibroblastic, reticular, adipocytic and osteogenic. Fibroblastic colonies, each derived from a single colony-forming unit fibroblastic (CFU-F), are formed when marrow cells are cultured in vitro. In vivo assays of tissue formed by CFU-F in open transplant or in diffusion chambers, have demonstrated that some CFU-F have a high ability for self renewal and multipotentiality whereas some have more limited potential. Preliminary investigations in vitro also support the hypothesis and have shown that CFU-F are a heterogeneous population of stem and progenitor cells and that their differentiation in vitro can be modified at the colony level. The stromal cells which survive and proliferate in vitro are highly dependent on culture conditions. The number and hierarchy of cell lines belonging to the stromal fibroblastic system are not yet fully elucidated and more specific markers and better assays for the different phenotypes are required before a greater understanding can be achieved. The possibility that the marrow stromal system is part of a wider stromal cell system of the body is proposed.


Antiretroviral Therapy for the Prevention of HIV-1 Transmission.
An interim analysis of data from the HIV Prevention Trials Network (HPTN) 052 trial showed that antiretroviral therapy (ART) prevented more than 96% of genetically linked infections caused by human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples. ART was then offered to all patients with HIV-1 infection (index participants). The study included more than 5 years of follow-up to assess the durability of such therapy for the prevention of HIV-1 transmission. We randomly assigned 1763 index participants to receive either early or delayed ART. In the early-ART group, 886 participants started therapy at enrollment (CD4+ count, 350 to 550 cells per cubic millimeter). In the delayed-ART group, 877 participants started therapy after two consecutive CD4+ counts fell below 250 cells per cubic millimeter or if an illness indicative of the acquired immunodeficiency syndrome (i.e., an AIDS-defining illness) developed. The primary study end point was the diagnosis of genetically linked HIV-1 infection in the previously HIV-1-negative partner in an intention-to-treat analysis. Index participants were followed for 10,031 person-years; partners were followed for 8509 person-years. Among partners, 78 HIV-1 infections were observed during the trial (annual incidence, 0.9%; 95% confidence interval [CI], 0.7 to 1.1). Viral-linkage status was determined for 72 (92%) of the partner infections. Of these infections, 46 were linked (3 in the early-ART group and 43 in the delayed-ART group; incidence, 0.5%; 95% CI, 0.4 to 0.7) and 26 were unlinked (14 in the early-ART group and 12 in the delayed-ART group; incidence, 0.3%; 95% CI, 0.2 to 0.4). Early ART was associated with a 93% lower risk of linked partner infection than was delayed ART (hazard ratio, 0.07; 95% CI, 0.02 to 0.22). No linked infections were observed when HIV-1 infection was stably suppressed by ART in the index participant. The early initiation of ART led to a sustained decrease in genetically linked HIV-1 infections in sexual partners. (Funded by the National Institute of Allergy and Infectious Diseases; HPTN 052 ClinicalTrials.gov number, NCT00074581 .).


Diallel Analysis of Early Leaf Spot (Cercospora arachidicola Hori) Disease Resistance in Groundnut.
Early leaf spot (ELS) is one of the major biotic constraints of groundnut production in West and Central Africa. A study using 6 × 6 F2 full diallel populations from six parents (NAMA, B188, PC79-79, QH243C, TS32-1, and CN94C) was conducted to assess the mode of inheritance of ELS resistance traits. The F2 and parents were grown in a randomized complete block design with three replications. Data was collected on ELS disease severity, and an area under disease progress curve (AUDPC) was estimated. The results revealed that additive and non-additive gene actions were involved in the inheritance of the ELS resistance traits, but additive gene action was predominant. Significant reciprocal cross effect was observed, suggesting cytoplasmic effect on ELS resistance. Graphical analysis also revealed the predominance of additive gene action for ELS resistance. The results suggest that early generation selection should be effective for ELS resistance. Looking at the distribution of array points along with the regression line, parental lines NAMA, PC79-79, and B188 would be suitable as good donors in an ELS disease resistance breeding program.


The Era of Multigene Panels Comes? The Clinical Utility of Oncotype DX and MammaPrint.
The AJCC Cancer Staging Manual, eighth edition published in late 2016, will become the new global guideline for cancer diagnosis and treatment from January 1, 2018. The new edition for the tumor staging system has numerous updates, including building up the prognostic stage group of tumors for the first time and adding a large number of non-anatomical factors into the prognostic evaluation. Oncotype DX and MammaPrint are two of the genomic predictors that will be part of routine clinical practice in the future. Numerous studies have proved the clinical utility of multigene panels in predicting clinical outcome and treatment response. Here we present our review of the studies on these multigene panels and their application to breast cancer.


Adenovirus L1 52- and 55-kilodalton proteins are present within assembling virions and colocalize with nuclear structures distinct from replication centers.
Analysis of a temperature-sensitive mutant, Ad5ts369, had indicated that the adenovirus L1 52- and 55-kDa proteins (52/55-kDa proteins) are required for the assembly of infectious virions. By using monoclonal antibodies directed against bacterially produced L1 52-kDa protein, the L1 52/55-kDa proteins were found to be differentially phosphorylated forms of a single 48-kDa polypeptide. Both phosphoforms were shown to be present within all suspected virus assembly intermediates (empty capsids, 50 to 100 molecules; young virions, 1 to 2 molecules) but not within mature virions. The mobilities of these proteins in polyacrylamide gels were affected by reducing agents, indicating that the 52/55-kDa proteins may exist as homodimers within the cell and within assembling particles. Immunofluorescence analysis revealed that the 52/55-kDa proteins localize to regions within the infected nucleus that are distinct from viral DNA replication centers, indicating that replication and assembly of viral components likely occur in separate nuclear compartments. Immunoelectron microscopic studies determined that the 52/55-kDa proteins are found in close association with structures that appear to contain assembling virions. These results are consistent with an active but transient role for the L1 products in assembly of the adenovirus particle, perhaps as scaffolding proteins.


Validity and reliability of the 6 minute walk in persons with fibromyalgia.
To assess the reliability and construct validity of the 6 minute walk (6MW) in persons with fibromyalgia (FM) and to determine an equation for predicting peak oxygen consumption (pVO2) from the distance covered in 6 minutes. Ninety-six women who met the American College of Rheumatology (ACR) criteria for FM were tested on the 6MW and the Fibromyalgia Impact Questionnaire (FIQ). A subset (n = 23) were tested on a separate day for pVO2 during a symptom-limited, incremental treadmill test. Twelve subjects repeated the 6MW five times over 10 days. Heart rate and rating of perceived exertion (RPE) were recorded for each walk. Intraclass correlations were used to determine the reliability of the 6MW. Validity was examined by correlating the 6MW with pVO2 and the FIQ. Body mass index (BMI) and 6MW were independent variables in a stepwise regression to predict pVO2. A significant increase in distance occurred from Walk 1 to Walk 2 (p = 0.000) with the distance maintained on the remaining walks (p = 0.148) The correlations of the 6MW with the FIQ and pVO2 were -0.325 and 0.657, respectively. The regression equation to predict pVO2 from 6MW distance and BMI was: pVO2 (ml/kg/min) = 21.48 + (-0.4316 x BMI) + [0.0304 x distance(m)] (R = 0.76, R2 = 0.66). When using the 6MW it is necessary to conduct a practice walk, with the second walk taken as the baseline measure. It was determined from the correlations that the 6MW cannot replace the FIQ as a measure of function. The 6MW may be used as an indicator of aerobic fitness, although obtaining VO2 by means of a graded exercise test is preferable.


From migration to settlement: the pathways, migration modes and dynamics of neurons in the developing brain.
Neuronal migration is crucial for the construction of the nervous system. To reach their correct destination, migrating neurons choose pathways using physical substrates and chemical cues of either diffusible or non-diffusible nature. Migrating neurons extend a leading and a trailing process. The leading process, which extends in the direction of migration, determines navigation, in particular when a neuron changes its direction of migration. While most neurons simply migrate radially, certain neurons switch their mode of migration between radial and tangential, with the latter allowing migration to destinations far from the neurons' site of generation. Consequently, neurons with distinct origins are intermingled, which results in intricate neuronal architectures and connectivities and provides an important basis for higher brain function. The trailing process, in contrast, contributes to the late stage of development by turning into the axon, thus contributing to the formation of neuronal circuits.


A controlled trial of inpatient and outpatient geriatric evaluation and management.
Over the past 20 years, both inpatient units and outpatient clinics have developed programs for geriatric evaluation and management. However, the effects of these interventions on survival and functional status remain uncertain. We conducted a randomized trial involving frail patients 65 years of age or older who were hospitalized at 11 Veterans Affairs medical centers. After their condition had been stabilized, patients were randomly assigned, according to a two-by-two factorial design, to receive either care in an inpatient geriatric unit or usual inpatient care, followed by either care at an outpatient geriatric clinic or usual outpatient care. The interventions involved teams that provided geriatric assessment and management according to Veterans Affairs standards and published guidelines. The primary outcomes were survival and health-related quality of life, measured with the use of the Medical Outcomes Study 36-Item Short-Form General Health Survey (SF-36), one year after randomization. Secondary outcomes were the ability to perform activities of daily living, physical performance, utilization of health services, and costs. A total of 1388 patients were enrolled and followed. Neither the inpatient nor the outpatient intervention had a significant effect on mortality (21 percent at one year overall), nor were there any synergistic effects between the two interventions. At discharge, patients assigned to the inpatient geriatric units had significantly greater improvements in the scores for four of the eight SF-36 subscales, activities of daily living, and physical performance than did those assigned to usual inpatient care. At one year, patients assigned to the outpatient geriatric clinics had better scores on the SF-36 mental health subscale, even after adjustment for the score at discharge, than those assigned to usual outpatient care. Total costs at one year were similar for the intervention and usual-care groups. In this controlled trial, care provided in inpatient geriatric units and outpatient geriatric clinics had no significant effects on survival. There were significant reductions in functional decline with inpatient geriatric evaluation and management and improvements in mental health with outpatient geriatric evaluation and management, with no increase in costs.


Treatment participation and medication adherence: effects on criminal justice costs of persons with mental illness.
Little empirical research has directly examined the extent to which early and consistent participation in outpatient services and adherence to prescribed psychotropic medications after a psychiatric hospitalization can help people with serious mental illnesses avoid arrest and incarceration and what impact this might have on state and local costs. The authors examined effects of medication adherence in the first 90 days after a psychiatric hospitalization among 1,367 adults with schizophrenia or bipolar disorder served by the public behavioral health systems of Miami-Dade County and Pinellas County in Florida. Better adherence was associated with lower subsequent criminal justice costs and greater use of treatment services. A modest investment in promoting treatment participation and medication adherence may reduce criminal justice involvement and costs for persons with serious mental illness.


Developing a Canadian prescribing practices network. Network Development Committee of the Canadian Prescribing Practices Network Project.
Expenditure on drug therapy in Canada has been growing at a faster rate than spending on any other aspect of health care. Increasing societal pressure to use scarce resources more efficiently, advances in communication technology and data indicating that there is room for improvement in drug prescribing suggest that the time has come for an organized linkage of the available drug-utilization and health-outcomes data-bases across the country. A national prescribing practices network would assist prescribers, researchers and policymakers to optimize prescribing with respect to both cost effectiveness and health outcomes. The authors outline the main concerns addressed in the 1994 report to the National Pharmaceutical Strategy and present the results of discussions by the Canadian Prescribing Practices Network Project with respect to the potential users and data sources of a national network and the communications technology on which it would rely.


Detection of hepatitis C virus transmission by use of DNA mass spectrometry.
The molecular detection of transmission of rapidly mutating pathogens such as hepatitis C virus (HCV) is commonly achieved by assessing the genetic relatedness of strains among infected patients. We describe the development of a novel mass spectrometry (MS)-based approach to identify HCV transmission. MS was used to detect products of base-specific cleavage of RNA molecules obtained from HCV polymerase chain reaction fragments. The MS-peak profiles were found to reflect variation in the HCV genomic sequence and the intrahost composition of the HCV population. Serum specimens originating from 60 case patients from 14 epidemiologically confirmed outbreaks and 25 unrelated controls were tested. Neighbor-joining trees constructed using MS-peak profile-based Hamming distances showed 100% accuracy, and linkage networks constructed using a threshold established from the Hamming distances between epidemiologically unrelated cases showed 100% sensitivity and 99.93% specificity in transmission detection. This MS-based approach is rapid, robust, reproducible, cost-effective, and applicable to investigating transmissions of other pathogens.


Targeting adenoviral vectors for enhanced gene therapy of uterine leiomyomas.
Is targeted adenovirus vector, Ad-SSTR-RGD-TK (Adenovirus -human somatostatin receptor subtype 2- arginine, glycine and aspartate-thymidine kinase), given in combination with ganciclovir (GCV) against immortalized human leiomyoma cells (HuLM) a potential therapy for uterine fibroids? Ad-SSTR-RGD-TK/GCV, a targeted adenovirus, effectively reduces cell growth in HuLM cells and to a significantly greater extent than in human uterine smooth muscle cells (UtSM). Uterine fibroids (leiomyomas), a major cause of morbidity and the most common indication for hysterectomy in premenopausal women, are well-defined tumors, making gene therapy a suitable and potentially effective non-surgical approach for treatment. Transduction of uterine fibroid cells with adenoviral vectors such as Ad-TK/GCV (herpes simplex virus thymidine kinase gene) decreases cell proliferation. An in vitro cell culture method was set up to compare and test the efficacy of a modified adenovirus vector with different multiplicities of infection in two human immortalized cell lines for 5 days. Immortalized human leiomyoma cells and human uterine smooth muscle cells were infected with different multiplicities of infection (MOI) (5-100 plaque-forming units (pfu)/cell) of a modified Ad-SSTR-RGD-TK vector and subsequently treated with GCV. For comparison, HuLM and UtSM cells were transfected with Ad-TK/GCV and Ad-LacZ/GCV. Cell proliferation was measured using the CyQuant assay in both cell types. Additionally, western blotting was used to assess the expression of proteins responsible for regulating proliferation and apoptosis in the cells. Transduction of HuLM cells with Ad-SSTR-RGD-TK/GCV at 5, 10, 50 and 100 pfu/cell decreased cell proliferation by 28, 33, 45, and 84%, respectively (P < 0.05) compared with untransfected cells, whereas cell proliferation in UtSM cells transfected with the same four MOIs of Ad-SSTR-RGD-TK/GCV compared with that of untransfected cells was decreased only by 8, 23, 25, and 28%, respectively (P < 0.01). Western blot analysis showed that, in comparison with the untargeted vector Ad-TK, Ad-SSTR-RGD-TK/GCV more effectively reduced expression of proteins that regulate the cell cycle (Cyclin D1) and proliferation (PCNA, Proliferating Cell Nuclear Antigen), and it induced expression of the apoptotic protein BAX, in HuLM cells. Results from this study need to be replicated in an appropriate animal model before testing this adenoviral vector in a human trial. Effective targeting of gene therapy to leiomyoma cells enhances its potential as a non-invasive treatment of uterine fibroids.


Imaging Evaluation of the Safe Region for Distal Locking Screw of Proximal Femoral Nail Anti-Rotation in Patients with Proximal Femoral Fracture.
BACKGROUND Proximal femoral nail anti-rotation (PFNA) is a standard femoral intertrochanteric fracture operation. Iatrogenic vascular injury, although uncommon, is a reported complication of PFNA surgery as well as a complication of hip fracture surgery. This study aimed to compare the safety and best use of the distal locking screw in 170 mm PFNA and 240 mm PFNA devices, and to determine the safe region for placement of the distal locking screw in PFNA surgery. MATERIAL AND METHODS A retrospective analysis of 100 patients with 170 mm PFNA and 80 patients with 240 mm PFNA were retrospectively analyzed. Two levels of PFNA distal locking screws were equally divided into three planes: I, II, III, for 170 mm PFNA devices and i, ii, iii for the 240 mm PRNA devices. The medial half of the femur was equally divided into eight regions: A to H. The distance between the outer femur and the superficial, the deep and the perforating femoral arteries (SFAs, DFAs, and PFAs), and angles between the reference line and the connection line between the femur center to each artery were measured. RESULTS SFAs and DFAs but not PFAs were found in risky or hazardous regions, and DFAs were obviously closer to the femur than SFAs and PFAs at the same level. In the region within 10 mm of the femur, no SFAs were found. The short nails (170 mm PFNA-II devices) were the closest to the DFAs region, indicating that the 170 mm PFNA-II nails are most likely to cause special vessel injury. The short nails were relatively more distant from the SFAs, which were located posteriorly to the long nails (240 mm PFNA-II). CONCLUSIONS The distal locking screw of the 170 mm PFNA device was more prone to damage the femoral deep artery when the two types of PFNA devices are compared in patients who were candidates for both types of devices.


Genome-wide loss-of-function analysis of deubiquitylating enzymes for zebrafish development.
Deconjugation of ubiquitin and/or ubiquitin-like modified protein substrates is essential to modulate protein-protein interactions and, thus, signaling processes in cells. Although deubiquitylating (deubiquitinating) enzymes (DUBs) play a key role in this process, however, their function and regulation remain insufficiently understood. The "loss-of-function" phenotype studies can provide important information to elucidate the gene function, and zebrafish is an excellent model for this goal. From an in silico genome-wide search, we found more than 90 putative DUBs encoded in the zebrafish genome belonging to six different subclasses. Out of them, 85 from five classical subclasses have been tested with morpholino (MO) knockdown experiments and 57 of them were found to be important in early development of zebrafish. These DUB morphants resulted in a complex and pleiotropic phenotype that, regardless of gene target, always affected the notochord. Based on the huC neuronal marker expression, we grouped them into five sets (groups I to V). Group I DUBs (otud7b, uchl3 and bap1) appear to be involved in the Notch signaling pathway based on the neuronal hyperplasia, while group IV DUBs (otud4, usp5, usp15 and usp25) play a critical role in dorsoventral patterning through the BMP pathway. We have identified an exhaustive list of genes in the zebrafish genome belonging to the five established classes of DUBs. Additionally, we performed the corresponding MO knockdown experiments in zebrafish as well as functional studies for a subset of the predicted DUB genes. The screen results in this work will stimulate functional follow-up studies of potential DUB genes using the zebrafish model system.


Outcome of revision of unicompartmental knee replacement.
Despite concerns regarding a higher risk of revision, unicompartmental knee arthroplasty (UKA) continues to be used as an alternative to total knee arthroplasty (TKA). There are, however, limited data on the subsequent outcome when a UKA is revised. We examined the survivorship for primary UKA procedures that have been revised. We used data from the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) to analyze the survivorship of 1,948 revisions of primary UKA reported to the Registry between September 1999 and December 2008. This was compared to the results of revisions of primary TKA reported during the same period where both the femoral and tibial components were revised. The Kaplan-Meier method for modeling survivorship was used. When a primary UKA was revised to another UKA (both major and minor revisions), it had a cumulative per cent revision (CPR) of 28 and 30 at 3 years, respectively. The CPR at 3 years when a UKA was converted to a TKA was 10. This is similar to the 3-year CPR (12) found earlier for primary TKA where both the femoral and tibial components were revised. When a UKA requires revision, the best outcome is achieved when it is converted to a TKA. This procedure does, however, have a major risk of re-revision, which is similar to the risk of re-revision of a primary TKA that has had both the femoral and tibial components revised.


Selective expansion of the monocytic lineage directed by bacterial infection.
CCR2-mediated recruitment of Ly6C(high) monocytes is essential for defense against a range of microbial pathogens. Although our understanding of monocyte trafficking to inflammatory sites is increasing, how innate immune inflammation influences monocyte development and maturation during microbial infection remains undefined. Herein, we demonstrate that infection with the intracellular bacterial pathogen Listeria monocytogenes specifically and selectively promotes monopoiesis. Systemic infection with virulent L. monocytogenes induces marked proliferation of bone marrow monocyte precursors and results in depletion of myeloid progenitors. Proliferation of monocyte precursors correlates with the intensity of systemic infection and is unaffected by the density of monocytes in the bone marrow. Although MyD88/Trif-mediated signaling is not required for early emigration of the mature monocyte population from the bone marrow, replenishment of monocyte populations depends on MyD88/Trif. Our studies demonstrate that TLR-mediated signals play an essential role in the maintenance of monocyte homeostasis during systemic bacterial infection.


Chloroplast Genome Analysis of Resurrection Tertiary Relict Haberlea rhodopensis Highlights Genes Important for Desiccation Stress Response.
Haberlea rhodopensis is a paleolithic tertiary relict species, best known as a resurrection plant with remarkable tolerance to desiccation. When exposed to severe drought stress, H. rhodopensis shows an ability to maintain the structural integrity of its photosynthetic apparatus, which re-activates easily upon rehydration. We present here the results from the assembly and annotation of the chloroplast (cp) genome of H. rhodopensis, which was further subjected to comparative analysis with the cp genomes of closely related species. H. rhodopensis showed a cp genome size of 153,099 bp, harboring a pair of inverted repeats (IR) of 25,415 bp separated by small and large copy regions (SSC and LSC) of 17,826 and 84,443 bp. The genome structure, gene order, GC content and codon usage are similar to those of the typical angiosperm cp genomes. The genome hosts 137 genes representing 70.66% of the plastome, which includes 86 protein-coding genes, 36 tRNAs, and 4 rRNAs. A comparative plastome analysis with other closely related Lamiales members revealed conserved gene order in the IR and LSC/SSC regions. A phylogenetic analysis based on protein-coding genes from 33 species defines this species as belonging to the Gesneriaceae family. From an evolutionary point of view, a site-specific selection analysis detected positively selected sites in 17 genes, most of which are involved in photosynthesis (e.g., rbcL, ndhF, accD, atpE, etc.). The observed codon substitutions may be interpreted as being a consequence of molecular adaptation to drought stress, which ensures an evolutionary advantage to H. rhodopensis.


Identification of a novel proinsulin-associated SNP and demonstration that proinsulin is unlikely to be a causal factor in subclinical vascular remodelling using Mendelian randomisation.
Increased proinsulin relative to insulin levels have been associated with subclinical atherosclerosis (measured by carotid intima-media thickness (cIMT)) and are predictive of future cardiovascular disease (CVD), independently of established risk factors. The mechanisms linking proinsulin to atherosclerosis and CVD are unclear. A genome-wide meta-analysis has identified nine loci associated with circulating proinsulin levels. Using proinsulin-associated SNPs, we set out to use a Mendelian randomisation approach to test the hypothesis that proinsulin plays a causal role in subclinical vascular remodelling. We studied the high CVD-risk IMPROVE cohort (n = 3345), which has detailed biochemical phenotyping and repeated, state-of-the-art, high-resolution carotid ultrasound examinations. Genotyping was performed using Illumina Cardio-Metabo and Immuno arrays, which include reported proinsulin-associated loci. Participants with type 2 diabetes (n = 904) were omitted from the analysis. Linear regression was used to identify proinsulin-associated genetic variants. We identified a proinsulin locus on chromosome 15 (rs8029765) and replicated it in data from 20,003 additional individuals. An 11-SNP score, including the previously identified and the chromosome 15 proinsulin-associated loci, was significantly and negatively associated with baseline IMTmean and IMTmax (the primary cIMT phenotypes) but not with progression measures. However, MR-Eggers refuted any significant effect of the proinsulin-associated 11-SNP score, and a non-pleiotropic SNP score of three variants (including rs8029765) demonstrated no effect on baseline or progression cIMT measures. We identified a novel proinsulin-associated locus and demonstrated that whilst proinsulin levels are associated with cIMT measures, proinsulin per se is unlikely to have a causative effect on cIMT.


The Effect of Race QCCJ of Puccinia graminis f. sp. tritici on Yield and Quality in Barley.
The progress of epidemics of race QCCJ of Puccinia graminis f. sp. tritici was examined in field plots of the barley cultivars Robust, Excel, Stander, Azure, Stark, Larker, Bonanza, and Steptoe. In addition, a potential source of resistance (cv. Diamond), and a susceptible line (ND11075) were included. Rust-free treatments were maintained to provide comparisons of grain yield and quality. Barleys with Rpg1, which confers resistance to races of P. graminis f. sp. tritici other than Pgt-QCCJ, were generally more resistant than cultivars or lines that lacked this gene. However the severity of losses indicated that under high disease pressure the resistance conferred by Rpg1 would not be effective. Yield reductions of up to 29% were recorded and were generally associated with reduced grain size and weight. The continued presence of Pgt-QCCJ as a component of the P. graminis population in the United States, since it was first detected in 1989, indicates that Pgt-QCCJ remains a threat to commercial barley production.


Treatment Strategy for Newly Diagnosed T1 High-grade Bladder Urothelial Carcinoma: New Insights and Updated Recommendations.
High-grade T1 (T1HG) bladder cancer (BCa) has a very high likelihood of disease recurrence and progression to muscle invasion. Radical cystectomy is considered the best chance at cure, albeit with a high risk of morbidity, and is overtreatment for some patients. Treatment with bacillus Calmette-Guerin (BCG) allows bladder preservation but may risk disease progression. To systematically review the current literature on the management of T1HG BCa and provide updated treatment recommendations. Medline, EMBASE, and Epub Ahead of Print databases were searched in November 2017 to identify observational cohort studies and controlled trials, between 1946 and 2017, associated with diagnosis, treatment, and prognosis of T1HG BCa. Clinical understaging and/or persistence of disease is not uncommon at initial transurethral resection (TUR); thus, a second re-TUR is recommended for cases with T1HG BCa. Patients electing a bladder preservation approach should undergo induction BCG therapy followed by a maintenance schedule, while patients with several high-risk features should consider immediate cystectomy and those with BCG-refractory or BCG-unresponsive disease should be considered for early cystectomy. Current phase I/II clinical trials for T1HG patients may offer future bladder preservation therapy approaches. T1HG tumours are heterogeneous in nature and challenging to treat. Bladder preservation with BCG induction and maintenance, or radical cystectomy is the current standard treatment modality of choice for these tumours. Promising therapies for BCG-unresponsive disease are currently under investigation. Patients with high-grade T1 bladder cancer are at a high risk of tumour recurrence and progression, requiring more aggressive treatment such as bladder removal. Bladder preservation therapies are available (and new therapies are being tested in clinical trials); however, patients should be aware that currently bladder removal is considered the best opportunity for cancer cure.


The evolution of codon preferences in Drosophila: a maximum-likelihood approach to parameter estimation and hypothesis testing.
Synonymous codon usage in related species may differ as a result of variation in mutation biases, differences in the overall strength and efficiency of selection, and shifts in codon preference-the selective hierarchy of codons within and between amino acids. We have developed a maximum-likelihood method to employ explicit population genetic models to analyze the evolution of parameters determining codon usage. The method is applied to twofold degenerate amino acids in 50 orthologous genes from D. melanogaster and D. virilis. We find that D. virilis has significantly reduced selection on codon usage for all amino acids, but the data are incompatible with a simple model in which there is a single difference in the long-term Ne, or overall strength of selection, between the two species, indicating shifts in codon preference. The strength of selection acting on codon usage in D. melanogaster is estimated to be |Nes| approximately 0.4 for most CT-ending twofold degenerate amino acids, but 1.7 times greater for cysteine and 1.4 times greater for AG-ending codons. In D. virilis, the strength of selection acting on codon usage for most amino acids is only half that acting in D. melanogaster but is considerably greater than half for cysteine, perhaps indicating the dual selection pressures of translational efficiency and accuracy. Selection coefficients in orthologues are highly correlated (rho = 0.46), but a number of genes deviate significantly from this relationship.


An Official American Thoracic Society/European Respiratory Society Workshop Report: Evaluation of Respiratory Mechanics and Function in the Pediatric and Neonatal Intensive Care Units.
Ready access to physiologic measures, including respiratory mechanics, lung volumes, and ventilation/perfusion inhomogeneity, could optimize the clinical management of the critically ill pediatric or neonatal patient and minimize lung injury. There are many techniques for measuring respiratory function in infants and children but very limited information on the technical ease and applicability of these tests in the pediatric and neonatal intensive care unit (PICU, NICU) environments. This report summarizes the proceedings of a 2011 American Thoracic Society Workshop critically reviewing techniques available for ventilated and spontaneously breathing infants and children in the ICU. It outlines for each test how readily it is performed at the bedside and how it may impact patient management as well as indicating future areas of potential research collaboration. From expert panel discussions and literature reviews, we conclude that many of the techniques can aid in optimizing respiratory support in the PICU and NICU, quantifying the effect of therapeutic interventions, and guiding ventilator weaning and extubation. Most techniques now have commercially available equipment for the PICU and NICU, and many can generate continuous data points to help with ventilator weaning and other interventions. Technical and validation studies in the PICU and NICU are published for the majority of techniques; some have been used as outcome measures in clinical trials, but few have been assessed specifically for their ability to improve clinical outcomes. Although they show considerable promise, these techniques still require further study in the PICU and NICU together with increased availability of commercial equipment before wider incorporation into daily clinical practice.


Anti-Inflammatory Effects of Omega-3 Fatty Acids in the Brain: Physiological Mechanisms and Relevance to Pharmacology.
Classically, polyunsaturated fatty acids (PUFA) were largely thought to be relatively inert structural components of brain, largely important for the formation of cellular membranes. Over the past 10 years, a host of bioactive lipid mediators that are enzymatically derived from arachidonic acid, the main n-6 PUFA, and docosahexaenoic acid, the main n-3 PUFA in the brain, known to regulate peripheral immune function, have been detected in the brain and shown to regulate microglia activation. Recent advances have focused on how PUFA regulate the molecular signaling of microglia, especially in the context of neuroinflammation and behavior. Several active drugs regulate brain lipid signaling and provide proof of concept for targeting the brain. Because brain lipid metabolism relies on a complex integration of diet, peripheral metabolism, including the liver and blood, which supply the brain with PUFAs that can be altered by genetics, sex, and aging, there are many pathways that can be disrupted, leading to altered brain lipid homeostasis. Brain lipid signaling pathways are altered in neurologic disorders and may be viable targets for the development of novel therapeutics. In this study, we discuss in particular how n-3 PUFAs and their metabolites regulate microglia phenotype and function to exert their anti-inflammatory and proresolving activities in the brain.


To see or not to see: investigating detectability of Ganges River dolphins using a combined visual-acoustic survey.
Detection of animals during visual surveys is rarely perfect or constant, and failure to account for imperfect detectability affects the accuracy of abundance estimates. Freshwater cetaceans are among the most threatened group of mammals, and visual surveys are a commonly employed method for estimating population size despite concerns over imperfect and unquantified detectability. We used a combined visual-acoustic survey to estimate detectability of Ganges River dolphins (Platanista gangetica gangetica) in four waterways of southern Bangladesh. The combined visual-acoustic survey resulted in consistently higher detectability than a single observer-team visual survey, thereby improving power to detect trends. Visual detectability was particularly low for dolphins close to meanders where these habitat features temporarily block the view of the preceding river surface. This systematic bias in detectability during visual-only surveys may lead researchers to underestimate the importance of heavily meandering river reaches. Although the benefits of acoustic surveys are increasingly recognised for marine cetaceans, they have not been widely used for monitoring abundance of freshwater cetaceans due to perceived costs and technical skill requirements. We show that acoustic surveys are in fact a relatively cost-effective approach for surveying freshwater cetaceans, once it is acknowledged that methods that do not account for imperfect detectability are of limited value for monitoring.


Is Salicylic Acid a Translocated Signal of Systemic Acquired Resistance in Tobacco?
Salicylic acid (SA) is a likely endogenous signal in the development of systemic acquired resistance (SAR) in some dicotyledonous plants. In tobacco mosaic virus (TMV)-resistant Xanthi-nc tobacco, SA levels increase systemically following the inoculation of a single leaf with TMV. To determine the extent to which systemic increases in SA result from SA export from the inoculated leaf, SA produced in TMV-inoculated or healthy leaves was noninvasively labeled with 18O2. Spatial and temporal distribution of 18O-SA indicated that most of the SA detected in the healthy tissues was synthesized in the inoculated leaf. No significant increase in the activity of benzoic acid 2-hydroxylase, the last enzyme involved in SA biosynthesis, was detected in upper uninoculated leaves, although the basal level of enzyme activity was relatively high. No increases in SA level, pathogenesis-related PR-1 gene expression, or TMV resistance in the upper uninoculated leaf were observed if the TMV-inoculated leaf was detached up to 60 hr after inoculation. Apart from the inoculated tissues, the highest increase in SA was observed in the leaf located directly above the inoculated leaf. The systemic SA increase observed during SAR may be explained by phloem transport of SA from the inoculation sites.


Comparative assessment of drug-eluting balloons in an advanced porcine model of coronary restenosis.
The advent of drug-eluting balloon (DEB) therapy has represented an important development in interventional cardiology. Nevertheless, preclinical data with this technology remain scant, and comparative studies have not previously been published. Bare metal stents were implanted in the coronary arteries of 15 pigs followed by balloon angioplasty. Animals were allocated to treatment with a 60-second inflation of one of four different balloon catheters: a conventional untreated plain angioplasty balloon (PBA, Biotronik AG), the Pantera Lux DEB (3.0 μg/mm2 paclitaxel; BTHC excipient, Biotronik AG), the Elutax DEB (2.0 μg/mm2 paclitaxel; no excipient; Aachen Resonance), or the SeQuent Please DEB (3.0 μg/mm2 paclitaxel; iopromide excipient: B. Braun). Twenty-eight days following balloon deployment, animals underwent repeat angiography for quantitative coronary angiography analysis and euthanasia for histopathologic assessment. By histology, the mean neointimal thickness was 0.44 ± 0.19 mm with PBA, 0.35 ± 0.13 mm with Pantera Lux , 0.61 ± 0.20 mm with Elutax , and 0.47 ± 0.21 mm with SeQuent Please DEB (p=0.02). In comparison with PBA, deployment of the Pantera Lux or the SeQuent Please DEB resulted in delayed healing characterised by significant increases in fibrin, neointimal cell vacuity and delayed re-endothelialisation. In conclusion, investigation of comparative DEB performance in a porcine model of advanced coronary restenosis reveals significant heterogeneity of neointimal suppression between the devices tested with numerically lowest values seen in the Pantera Lux group. On the other hand, evidence of delayed healing was observed in the most effective DEB groups.


Hyperchaos and multistability in the model of two interacting microbubble contrast agents.
We study nonlinear dynamics of two coupled contrast agents that are micrometer size gas bubbles encapsulated into a viscoelastic shell. Such bubbles are used for enhancing ultrasound visualization of blood flow and have other promising applications like targeted drug delivery and noninvasive therapy. Here, we consider a model of two such bubbles interacting via the Bjerknes force and exposed to an external ultrasound field. We demonstrate that in this five-dimensional nonlinear dynamical system, various types of complex dynamics can occur, namely, we observe periodic, quasiperiodic, chaotic, and hypechaotic oscillations of bubbles. We study the bifurcation scenarios leading to the onset of both chaotic and hyperchaotic oscillations. We show that chaotic attractors in the considered system can appear via either the Feigenbaum cascade of period-doubling bifurcations or the Afraimovich-Shilnikov scenario of torus destruction. For the onset of hyperchaotic dynamics, we propose a new bifurcation scenario, which is based on the appearance of a homoclinic chaotic attractor containing a saddle-focus periodic orbit with its two-dimensional unstable manifold. Finally, we demonstrate that the dynamics of two bubbles can be essentially multistable, i.e., various combinations of the coexistence of the above mentioned attractors are possible in this model. These cases include the coexistence of a hyperchaotic regime with an attractor of any other remaining type. Thus, the model of two coupled gas bubbles provides a new example of physically relevant system with multistable hyperchaos.