Early childhood development and social mobility.
Steven Barnett and Clive Belfield examine the effects of preschool education on social mobility in the United States. They note that under current policy three- and four-year-old children from economically and educationally disadvantaged families have higher preschool attendance rates than other children. But current programs fail to enroll even half of poor three- and four-year-olds. Hispanics and children of mothers who drop out of school also participate at relatively low rates. The programs also do little to improve learning and development. The most effective programs, they explain, are intensive interventions such as the model Abecedarian and Perry Preschool programs, which feature highly qualified teachers and small group sizes. State preschool programs with the highest standards rank next, followed by Head Start and the average state program, which produce effects ranging from one-tenth to one-quarter of those of the best programs. Typical child care and family support programs rank last. Barnett and Belfield point out that preschool programs raise academic skills on average, but do not appear to have notably different effects for different groups of children, and so do not strongly enhance social mobility. In such areas as crime, welfare, and teen parenting, however, preschool seems more able to break links between parental behaviors and child outcomes. Increased investment in preschool, conclude Barnett and Belfield, could raise social mobility. Program expansions targeted to disadvantaged children would help them move up the ladder, as would a more universal set of policies from which disadvantaged children gained disproportionately. Increasing the educational effectiveness of early childhood programs would provide for greater gains in social mobility than increasing participation rates alone. The authors observe that if future expansions of preschool programs end up serving all children, not just the poorest, society as a whole would gain. Benefits would exceed costs and there would be more economic growth, but relative gains for disadvantaged children would be smaller than absolute gains because there would be some (smaller) benefits to other children.


Economic transition and environmental sustainability: effects of economic restructuring on air pollution in the Russian Federation.
Economic liberalization in former socialist countries may have various implications for their environmental sustainability. Positive effects of this process are potentially associated with improved efficiency, investments into cleaner technologies, responsiveness to environmentally aware markets, and ending subsidies to heavy industries. On the other hand, market liberalization may result in weaker environmental controls, economic instabilities distracting attention from environmental issues, and increasing orientation towards profit-making leading to more intensive exploitation of natural resources. In addition, trade liberalization may result in shifts towards more pollution and resource-intensive industries. This article seeks to quantify effects of economic restructuring in Russia on air pollution from productive economic sectors in the 1990s. Air pollution in Russia had significantly declined in 1991-1999, however, this decline was largely due to economic decline, as the overall pollution intensity of the economy had decreased only slightly. The factors that affected the pollution intensity are: (1) a decrease in the combined share of industrial and transport activities in the economy and (2) changing pollution intensities of the industrial and transport sectors. The pollution intensity of the Russian industry had remained relatively stable during the 1990s. This was the result of the two opposite and mutually canceling trends: (a) increasing shares of pollution-intensive branches such as metal smelting and oil production vs. less pollution intensive manufacturing and (b) decline in pollution intensities within the industrial branches. The article proposes a methodology by which the contribution of both factors to the overall pollution intensity of the industrial sector can be quantified. The pollution intensity of the Russian transport sector appears to have declined in the first half of the 1990s and increased in the second half. The most recent trend can be explained by a rising proportion of private motorcars used for transportation of people and goods instead of traditional rail and other public transport. The findings of the paper demonstrate that shifts towards more pollution-, resource- and energy-intensive industries as a result of economic liberalization emerges as a significant negative factor of the process of economic transition threatening sustainability of emerging market economies. A research agenda to further investigate these impacts is proposed.


Third ventricular chordoid glioma: a distinct clinicopathologic entity.
We have encountered a series of 8 third ventricular neoplasms with a distinctive chordoid appearance that appear to represent a clinicopathologic entity. The tumors occurred in 7 females and 1 male, ranging in age from 31 to 70 years. In all cases, imaging studies showed a large well-circumscribed third ventricular mass; a cystic component was noted in 2. The tumors consisted of cords and clusters of cohesive, oval-to-polygonal epithelioid cells with abundant eosinophilic cytoplasm, relatively uniform round-to-oval nuclei, and inconspicuous nucleoli. Mitotic activity was absent. The stroma consisted of scant, coarse fibrillar processes, as well as prominent, slightly basophilic, extracellular mucin resembling that in chordomas. Throughout the tumor, and surrounding its well-defined borders, were infiltrates of mature lymphocytes and plasma cells. Russell bodies were prominent in the latter. Adjacent brain tissue showed reactive changes with gliosis and numerous Rosenthal fibers. Immunohistochemically, tumor cells were strongly reactive for GFAP and vimentin, but negative or only weakly staining for EMA. The MIB-1 labeling index was approximately 1%. Ultrastructural examination of 4 cases revealed focal microvilli, scattered "intermediate" junctions, and focal basal lamina formation. Neither desmosomes nor cilia were seen. Total resections were achieved in 2 cases; only subtotal removals were achieved in 6. Subsequent tumor enlargement was noted in 3 of the 6 patients with incomplete resection, and of these, two died at post-operative intervals of 8 months and 3 years. The other patient survives 4 years post-operatively with stable residual disease. Of the 2 patients with total resection, 1 was lost to follow-up; the other, during a brief follow-up period, did well without evidence of recurrence.


Physical Activity from Early Adulthood and Risk of Prostate Cancer: A 24-Year Follow-Up Study among Icelandic Men.
Physical activity in adult life may reduce prostate cancer risk. Data are scarce on the role of activity during early adulthood, as well as combined recreational and occupational physical activity on prostate cancer risk and mortality. We undertook a prospective study of 8,221 Icelandic men (born 1907 to 1935) in the population-based Reykjavik Study. At enrollment, between 1967 and 1987, the men provided information on regular recreational physical activity since the age of 20 years as well as current occupational activity. Through linkage to nationwide cancer and mortality registers, the men were followed for prostate cancer diagnosis and mortality through 2009. We used Cox models to calculate the relative risk of prostate cancer by level of physical activity. During a mean follow-up of 24.8 years, 1,052 men were diagnosed with prostate cancer, of whom 349 had advanced disease (stage 3+ or prostate cancer death). Neither recreational nor occupational physical activity was, independently or combined, associated with overall or localized prostate cancer. Compared with physically inactive men, we observed a nonsignificant lower risk of advanced prostate cancer [HR, 0.67; 95% confidence interval (CI), 0.42-1.07] among men reporting both recreational and occupational physical activities (P value for interaction = 0.03). Awaiting confirmation in larger studies with detailed assessment of physical activity, our data suggest that extensive physical activity beginning in early adulthood may reduce the risk of advanced prostate cancer.


Nucleotide sequence of the enterotoxin B gene from Staphylococcus aureus.
The complete nucleotide sequence of the enterotoxin B gene from Staphylococcus aureus, as well as the 5' and 3' flanking regions, was determined. Starting from an ATG initiator codon, an open reading frame encoded the enterotoxin B precursor that consisted of 266 amino acids (Mr, 31,400). The 5' terminal portion of the gene encodes a signal peptide 27 amino acids long. The deduced amino acid sequence matched, with a few exceptions, the published amino acid sequence of enterotoxin B. The structural gene was flanked on the 5' side by a promoter-like sequence and on the 3' side by a palindromic structure followed by a thymine-rich region that resembled a transcription termination signal. Downstream from the entB gene were two overlapping open reading frames corresponding to 134 and 185 amino acids in the opposite orientation. The signal sequence of the enterotoxin B precursor resembled that of other secreted proteins found in other bacteria.


Two-dimensional waveguide modeling of leaky-mode arrays.
We examine the structure and modal gains of the leaky modes of an infinite periodic index-guided array by direct solution of the two-dimensional Helmholtz equation. These findings serve to validate the physical insights suggested by our previous calculations based on the effective-index method and, in particular, confirm the concept of guidewidth tailoring for affecting fundamental-mode operation of these devices at high power levels. Our newer model also provides new insights into the mode-selection mechanism and demonstrates clearly the necessity of a full twodimensional treatment if one is to describe the mode profiles or their relative gains accurately.


Wnt11-R, a protein closely related to mammalian Wnt11, is required for heart morphogenesis in Xenopus.
Wnt11 is a secreted protein that signals through the non-canonical planar cell polarity pathway and is a potent modulator of cell behavior and movement. In human, mouse, and chicken, there is a single Wnt11 gene, but in zebrafish and Xenopus, there are two genes related to Wnt11. The originally characterized Xenopus Wnt11 gene is expressed during early embryonic development and has a critical role in regulation of gastrulation movements. We have identified a second Xenopus Wnt11-Related gene (Wnt11-R) that is expressed after gastrulation. Sequence comparison suggests that Xenopus Wnt11-R, not Wnt11, is the ortholog of mammalian and chicken Wnt11. Xenopus Wnt11-R is expressed in neural tissue, dorsal mesenchyme derived from the dermatome region of the somites, the brachial arches, and the muscle layer of the heart, similar to the expression patterns reported for mouse and chicken Wnt11. Xenopus Wnt11-R exhibits biological properties similar to those previously described for Xenopus Wnt11, in particular the ability to activate Jun-N-terminal kinase (JNK) and to induce myocardial marker expression in ventral marginal zone (VMZ) explants. Morpholino inhibition experiments demonstrate, however, that Wnt11-R is not required for cardiac differentiation, but functions in regulation of cardiac morphogenesis. Embryos with reduced Wnt11-R activity exhibit aberrant cell-cell contacts within the myocardial wall and defects in fusion of the nascent heart tube.


Identification of a subset of human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus strains able to exploit an alternative coreceptor on untransformed human brain and lymphoid cells.
The chemokine receptors CCR5 and CXCR4 are the major coreceptors for human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). At least 12 other chemokine receptors or close relatives support infection by particular HIV and SIV strains on CD4(+) transformed indicator cell lines in vitro. However, the role of these alternative coreceptors in vivo is presently thought to be insignificant. Infection of cell lines expressing high levels of recombinant CD4 and coreceptors thus does not provide a true indication of coreceptor use in vivo. We therefore tested primary untransformed cell cultures that lack CCR5 and CXCR4, including astrocytes and brain microvascular endothelial cells (BMVECs), for naturally expressed alternative coreceptors functional for HIV and SIV infection. An adenovirus vector (Ad-CD4) was used to express CD4 in CD4(-) astrocytes and thus confer efficient infection if a functional coreceptor is present. Using a large panel of viruses with well-defined coreceptor usage, we identified a subset of HIV and SIV strains able to infect two astrocyte cultures derived from adult brain tissue. Astrocyte infection was partially inhibited by several chemokines, indicating a role for the chemokine receptor family in the observed infection. BMVECs were weakly positive for CD4 but negative for CCR5 and CXCR4 and were susceptible to infection by the same subset of isolates that infected astrocytes. BMVEC infection was efficiently inhibited by the chemokine vMIP-I, implicating one of its receptors as an alternative coreceptor for HIV and SIV infection. Furthermore, we tested whether the HIV type 1 and type 2 strains identified were able to infect peripheral blood mononuclear cells (PBMCs) via an alternative coreceptor. Several strains replicated in Delta32/Delta32 CCR5 PBMCs with CXCR4 blocked by AMD3100. This AMD3100-resistant replication was also sensitive to vMIP-I inhibition. The nature and potential role of this alternative coreceptor(s) in HIV infection in vivo is discussed.


Effect of mirthful laughter on vascular function.
In contrast to the well-established scientific evidence linking negative emotional states (e.g., depression, anxiety, or anger) to increased risk for cardiovascular disease, much less is known about the association between positive emotional states (e.g., laughter, happiness) and cardiovascular health. We determined the effects of mirthful laughter, elicited by watching comic movies, on endothelial function and central artery compliance. Seventeen apparently healthy adults (23 to 42 years of age) watched 30 minutes of a comedy or a documentary (control) on separate days (crossover design). Heart rate and blood pressure increased significantly while watching the comedy, whereas no such changes were seen while watching the documentary. Ischemia-induced brachial artery flow-mediated vasodilation (by B-mode ultrasound imaging) increased significantly after watching the comedy (17%) and decreased with watching the documentary (-15%). Carotid arterial compliance (by simultaneous application of ultrasound imaging and applanation tonometry) increased (10%) significantly immediately after watching the comedy and returned to baseline 24 hours after the watching, whereas it did not change significantly throughout the documentary condition. Comedy-induced changes in arterial compliance were significantly associated with baseline flow-mediated dilation (r = 0.63). These results suggest that mirthful laughter elicited by comic movies induces beneficial impact on vascular function.


Prescription for education: development, evaluation, and implementation of a successful interprofessional education program for adults with inflammatory arthritis.
To assess the feasibility of recruitment and standardize care delivery for an interprofessional program for inflammatory arthritis education (Prescription for Education, or RxEd), and to explore outcomes relevant to arthritis patient education. A patient-based needs assessment and ongoing patient feedback guided program development. An interprofessional team was involved in developing program content and delivering and adapting the program to patient needs. A quasiexperimental, waitlisted control with crossover design was used to evaluate the program. Data were collected at baseline, immediately following intervention, at 6 months (when the crossover control group received intervention), and at 1 year. Self-report measures included demographics, disorder-related data, Arthritis Self-efficacy Scale, arthritis knowledge, coping efficacy, and illness intrusiveness. Analysis included baseline comparisons and longitudinal trends; direct between-group comparison at 6 months; and generalized estimating equations (GEE) analysis to evaluate the main effect of the intervention on the primary outcome (arthritis self-efficacy) and secondary outcomes. Program modifications based on patient input made recruitment possible. Forty-two persons participated (including 19 controls), with 93% followup at 1 year. Comparison of change shows moderate effect sizes (standardized effect size 0.5 to 0.7). GEE analysis showed significant main effect, before to after the program, in both groups for primary outcome (arthritis self-efficacy) and most secondary outcomes. Program feasibility was dependent on patient feedback. Our pilot study provides evidence that the RxEd program is feasible and improves arthritis self-efficacy and other outcomes.


Control of glycolytic enzyme binding: effect of changing enzyme substrate concentrations on in vivo enzyme distributions.
The effect of changing concentrations of glycolytic intermediates on the binding of phosphofructokinase, aldolase and pyruvate kinase to cellular particulate matter was investigated. Concentrations of glycolytic intermediates were altered by adding 2 mM iodoacetic acid (IAA) to an incubation medium containing tissues isolated from the channelled whelk Busycon canaliculatum. Iodoacetic acid inhibited glyceraldehyde 3-phosphate dehydrogenase activity causing a 100-400 fold increase in the concentration of fructose 1,6-bisphosphate as well as 3-20 fold increases in glucose 6-phosphate, fructose 6-phosphate, and dihydroxyacetone phosphate levels depending on the experimental protocol. Cellular pH values were not statistically different in the presence of IAA. Measurement of enzyme binding to particulate matter showed that the binding of phosphofructokinase, aldolase and pyruvate kinase was unaffected by iodoacetic acid under any experimental condition. These results show that changes in the tissue concentrations of enzyme substrates and products do not regulate enzyme binding to particulate matter in the cell.


House screening with insecticide-treated netting provides sustained reductions in domestic populations of Aedes aegypti in Merida, Mexico.
There is a need for effective methods to control Aedes aegypti and prevent the transmission of dengue, chikungunya, yellow fever and Zika viruses. Insecticide treated screening (ITS) is a promising approach, particularly as it targets adult mosquitoes to reduce human-mosquito contact. A cluster-randomised controlled trial evaluated the entomological efficacy of ITS based intervention, which consisted of the installation of pyrethroid-impregnated long-lasting insecticide-treated netting material fixed as framed screens on external doors and windows. A total of 10 treatment and 10 control clusters (100 houses/cluster) were distributed throughout the city of Merida, Mexico. Cross-sectional entomological surveys quantified indoor adult mosquito infestation at baseline (pre-intervention) and throughout four post-intervention (PI) surveys spaced at 6-month intervals corresponding to dry/rainy seasons over two years (2012-2014). A total of 844 households from intervention clusters (86% coverage) were protected with ITS at the start of the trial. Significant reductions in the indoor presence and abundance of Ae. aegypti adults (OR = 0.48 and IRR = 0.45, P<0.05 respectively) and the indoor presence and abundance of Ae. aegypti female mosquitoes (OR = 0.47 and IRR = 0.44, P<0.05 respectively) were detected in intervention clusters compared to controls. This high level of protective effect was sustained for up to 24 months PI. Insecticidal activity of the ITS material declined with time, with ~70% mortality being demonstrated in susceptible mosquito cohorts up to 24 months after installation. The strong and sustained entomological impact observed in this study demonstrates the potential of house screening as a feasible, alternative approach to a sustained long-term impact on household infestations of Ae. aegypti. Larger trials quantifying the effectiveness of ITS on epidemiological endpoints are warranted and therefore recommended.


Cytotoxic T cells from human immunodeficiency virus type 2-infected patients frequently cross-react with different human immunodeficiency virus type 1 clades.
Knowledge of immune mechanisms responsible for the cross-protection between highly divergent viruses such as human immunodeficiency virus type 1 (HIV-1) and HIV-2 may contribute to an understanding of whether virus variability may be overcome in the design of vaccine candidates which are broadly protective across the HIV subtypes. We demonstrate that despite the significant difference in virus amino acid sequence, the majority of HIV-2-infected individuals with different HLA molecules possess a dominant cytotoxic T-cell response which is able to recognize HIV-1 Gag protein. Furthermore, HLA-B5801-positive subjects show broad cross-recognition of HIV-1 subtypes since they mounted a T-cell response that tolerated extensive amino acid substitutions within HLA-B5801-restricted HIV-1 and HIV-2 epitopes. These results suggests that HLA-B5801-positive HIV-2-infected individuals have an enhanced ability to react with HIV-1 that could play a role in cross-protection.


Use of Complementary and Alternative Medicine in Cancer Patients: A Prospective Questionnaire-Based Study in an Oncological Outpatient Clinic.
A questionnaire-based prospective study was conducted to evaluate the current use of complementary and alternative medicine (CAM) in a hemato-oncological outpatient clinic. A multiple-choice questionnaire was designed to assess the use of CAM in a hemato-oncological outpatient clinic. It consisted of questions on sociodemographic and general patient data, and of different kind of questions concerning the use of CAM, including disclosure rates to oncologists and general physicians. The data was analyzed with SAS and a p-value < 0.05 was considered as statistically significant. 46 out of 251 patients (18%) indicated to use CAM. 62 out of all patients (25%) discussed the topic with their general physician or oncologist. Praying or nutritional supplements were the most often used type of CAM. 95 of all participating patients found that the use of CAM could be helpful. The findings of our monocentric study in an outpatient setting do not support the relatively high percentage of CAM users described in the current literature. Nevertheless, CAM needs to be defined more clearly, in order to increase the patients' awareness of CAM.


Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER.
MicroRNAs are small regulatory RNAs that post transcriptionally control gene expression. Reduced expression of DICER, the enzyme involved in microRNA processing, is frequently observed in cancer and is associated with poor clinical outcome in various malignancies. Yet, the underlying mechanisms are not well understood. Here we identify tumour hypoxia as a regulator of DICER expression in large cohorts of breast cancer patients. We show that DICER expression is suppressed by hypoxia through an epigenetic mechanism that involves inhibition of oxygen-dependent H3K27me3 demethylases KDM6A/B and results in silencing of the DICER promoter. Subsequently, reduced miRNA processing leads to derepression of the miR-200 target ZEB1, stimulates the epithelial to mesenchymal transition and ultimately results in the acquisition of stem cell phenotypes in human mammary epithelial cells. Our study uncovers a previously unknown relationship between oxygen-sensitive epigenetic regulators, miRNA biogenesis and tumour stem cell phenotypes that may underlie poor outcome in breast cancer.


Charting brain growth in tandem with brain templates at school age.
Brain growth charts and age-normed brain templates are essential resources for researchers to eventually contribute to the care of individuals with atypical developmental trajectories. The present work generates age-normed brain templates for children and adolescents at one-year intervals and the corresponding growth charts to investigate the influences of age and ethnicity using a common pediatric neuroimaging protocol. Two accelerated longitudinal cohorts with the identical experimental design were implemented in the United States and China. Anatomical magnetic resonance imaging (MRI) of typically developing school-age children (TDC) was obtained up to three times at nominal intervals of 1.25 years. The protocol generated and compared population- and age-specific brain templates and growth charts, respectively. A total of 674 Chinese pediatric MRI scans were obtained from 457 Chinese TDC and 190 American pediatric MRI scans were obtained from 133 American TDC. Population- and age-specific brain templates were used to quantify warp cost, the differences between individual brains and brain templates. Volumetric growth charts for labeled brain network areas were generated. Shape analyses of cost functions supported the necessity of age-specific and ethnicity-matched brain templates, which was confirmed by growth chart analyses. These analyses revealed volumetric growth differences between the two ethnicities primarily in lateral frontal and parietal areas, regions which are most variable across individuals in regard to their structure and function. Age- and ethnicity-specific brain templates facilitate establishing unbiased pediatric brain growth charts, indicating the necessity of the brain charts and brain templates generated in tandem. These templates and growth charts as well as related codes have been made freely available to the public for open neuroscience (https://github.com/zuoxinian/CCS/tree/master/H3/GrowthCharts).


Isolation of four new CoII/CoIII and NiII complexes with a pentadentate Schiff base ligand: syntheses, structural descriptions and magnetic studies.
In this paper we report the temperature and pH dependent syntheses and systematic characterization of four new Co(II)/Co(III) and Ni(II) complexes with a pentadentate Schiff base ligand H(3)L obtained by condensing 1,3,-diaminopropan-2-ol with 2-hydroxyacetophenone in 1:2 molar ratio. The room temperature syntheses involving Co(II) and Ni(II) nitrates and the ligand H(3)L lead to the isolation of the dinuclear species [Co(2)L(2)(H(2)O)] (1), and the mononuclear complex [Ni(LH)] (3), respectively, whereas refluxing at basic pH leads to the tetranuclear complexes, [Co(II)(2)Co(III)(2)L(2)(μ(3)-OMe)(2)(NO(3))(H(2)O)(2)]NO(3)·2(H(2)O) (2), and [Ni(4)L(2)(μ(3)-OMe)(2)(H(2)O)(2)]·2H(2)O (4). 1 is found to be a simple mono alkoxo-bridged Co(III) dinuclear species, whereas 2 and 4 are both rhomb-like tetrameric complexes with double oxo bridges and μ(3)-methoxo bridges, derived from the methanol solvent, in an open dicubane arrangement. Moreover 2 shows six coordinate ordered Co(II) and Co(III) ions and 4 has both six- and five-coordinate Ni(II) centers. Compound 3 is assigned a tentative mononuclear structure based on IR, UV-Vis spectroscopic, (1)H-NMR and ESI mass study results and is supposed to have one Ni(II) center coordinated with a ligand fragment in square planar geometry. The variable temperature magnetic susceptibility study for 2 and 4 is performed which indicate for both 2 and 4 the presence of intracluster dominant ferromagnetic interactions.


Intracellular pattern recognition receptors in the host response.
The innate immune system relies on its capacity to rapidly detect invading pathogenic microbes as foreign and eliminate them. Indeed, Toll-like receptors are a class of membrane receptors that sense extracellular microbes and trigger anti-pathogen signalling cascades. Recently, intracellular microbial sensors have also been identified, including NOD-like receptors and the helicase-domain-containing antiviral proteins RIG-I and MDA5. Some of these cytoplasmic molecules sense microbial, as well as non-microbial, danger signals, but the mechanisms of recognition used by these sensors remain poorly understood. Nonetheless, it is apparent that these proteins are likely to have critical roles in health and disease.


A peer navigation intervention to prevent HIV among mixed immigrant status Latinx GBMSM and transgender women in the United States: outcomes, perspectives and implications for PrEP uptake.
The Latinx population in the United States is disproportionately affected by HIV. Our community-based participatory research partnership developed, implemented and evaluated a Spanish-language peer navigation intervention designed to increase HIV testing and condom use among social networks of immigrant Spanish-speaking Latinx gay, bisexual and other men who have sex with men (GBMSM) and transgender women (TW). We randomized 21 social networks of Latinx GBMSM and TW, ages 18-55 years, to the intervention, known as HOLA, or a waitlist control group. Social network participants (n = 166) completed structured assessments at baseline and 12-month follow-up (24 months after baseline). Follow-up retention was 95%. Individual in-depth interviews with a sample of participants documented their intervention-related experiences, needs, and priorities to inform future research. At follow-up, HOLA participants reported increased HIV testing (adjusted odds ratio = 8.3; 95% CI = 3.0-23.0; P < 0.0001). All study participants reported increased condom use; there was no significant difference between HOLA and waitlist control participants. In-depth interviews identified critical intervention elements and impacts and community needs and priorities. The HOLA intervention is effective for increasing HIV testing among Latinx GBMSM and TW, an initial step within the HIV prevention and care continua, and may be adaptable to promote pre-exposure prophylaxis uptake.


Inclusion of filter modulation in synthetic-discriminant-function construction.
A technique in which the filter modulation is included in the synthesis of a synthetic-discriminant-function matched spatial filter (SDF MSF) is presented. In the filter synthesis, a system of simultaneous nonlinear equations is solved with an iteration procedure. A computer simulation of the new method using thresholded images of the Space Shuttle over a range of aspect angles was performed for phase-only filters (POFs) and binary-phase-only filters (BPOFs). The filters constructed are capable of obtaining the specified peak-correlation response to within 1% with a high signal-to-clutter-ratio for the one-class problem, the two-class problem, and the multilevel problem. In contrast, conventional projection SDF POFs and BPOFs are unable to produce the desired peak-correlation response.


Conceptualization and measurement of homosexuality in sex surveys: a critical review.
This article reviews major national population sex surveys that have asked questions about homosexuality focusing on conceptual and methodological issues, including the definitions of sex, the measured aspects of homosexuality, sampling and interviewing technique, and questionnaire design. Reported rates of major measures of same-sex attraction, behavior, partners, and sexual identity from surveys are also presented and compared. The study of homosexuality in surveys has been shaped by the research traditions and questions ranging from sexology to the epidemiology of HIV/AIDS. Sexual behavior has been a central topic at least since Kinsey. Issues of sexual attraction and/or orientation and sexual identity have emerged more recently. Differences in the treatment of men and women in the design and analysis of surveys as well as in the reported rates in different surveys, in different countries and time periods are also presented and discussed. We point out the importance of the consideration of both methodological and social change issues in assessing such differences.


Rapid thermal responses and thermal tolerance in adult codling moth Cydia pomonella (Lepidoptera: Tortricidae).
In order to preserve key activities or improve survival, insects facing variable and unfavourable thermal environments may employ physiological adjustments on a daily basis. Here, we investigate the survival of laboratory-reared adult Cydia pomonella at high or low temperatures and their responses to pre-treatments at sub-lethal temperatures over short time-scales. We also determined critical thermal limits (CTLs) of activity of C. pomonella and the effect of different rates of cooling or heating on CTLs to complement the survival assays. Temperature and duration of exposure significantly affected adult C. pomonella survival with more extreme temperatures and/or longer durations proving to be more lethal. Lethal temperatures, explored between -20 °C to -5 °C and 32 °C to 47 °C over 0.5, 1, 2, 3 and 4h exposures, for 50% of the population of adult C. pomonella were -12 °C for 2h and 44 °C for 2h. Investigation of rapid thermal responses (i.e. hardening) found limited low temperature responses but more pronounced high temperature responses. For example, C. pomonella pre-treated for 2h at 5 °C improved survival at -9 °C for 2h from 50% to 90% (p<0.001). At high temperatures, pre-treatment at 37 °C for 1h markedly improved survival at 43°C for 2h from 20% to 90% (p<0.0001). We also examined cross-tolerance of thermal stressors. Here, low temperature pre-treatments did not improve high temperature survival, while high temperature pre-treatment (37°C for 1h) significantly improved low temperature survival (-9 °C for 2h). Inducible cross-tolerance implicates a heat shock protein response. Critical thermal minima (CT min) were not significantly affected by cooling at rates of 0.06, 0.12 and 0.25 °C min(-1) (CT min range: 0.3-1.3 °C). By contrast, critical thermal maxima (CTmax) were significantly affected by heating at these rates and ranged from 42.5 to 44.9 °C. In sum, these results suggest pronounced plasticity of acute high temperature tolerance in adult C. pomonella, but limited acute low temperature responses. We discuss these results in the context of local agroecosystem microclimate recordings. These responses are significant to pest control programmes presently underway and have implications for understanding the evolution of thermal tolerance in these and other insects.


Infodemics and infodemiology: a short history, a long future.
An "infodemic" is defined as "an overabundance of information - some accurate and some not - occurring during an epidemic". This paper describes the characteristics of an infodemic, which combines an inordinately high volume of information (leading to problems relating to locating the information, storage capacity, ensuring quality, visibility and validity) and rapid output (making it hard to assess its value, manage the gatekeeping process, apply results, track its history, and leading to a waste of effort). This is bound up with the collateral growth of misinformation, disinformation and malinformation. Solutions to the problems posed by an infodemic will be sought in improved technology and changed social and regulatory frameworks. One solution could be a new trusted top-level domain for health information. The World Health Organization has so far made two unsuccessful attempts to create such a domain, but it is suggested this could be attempted again, in the light of the COVID-19 infodemic experience. The vital role of reliable information in public health should also be explicitly recognized in the Sustainable Development Goals, with explicit targets. All countries should develop knowledge preparedness plans for future emergencies.


Single molecule sequencing and genome assembly of a clinical specimen of Loa loa, the causative agent of loiasis.
More than 20% of the world's population is at risk for infection by filarial nematodes and >180 million people worldwide are already infected. Along with infection comes significant morbidity that has a socioeconomic impact. The eight filarial nematodes that infect humans are Wuchereria bancrofti, Brugia malayi, Brugia timori, Onchocerca volvulus, Loa loa, Mansonella perstans, Mansonella streptocerca, and Mansonella ozzardi, of which three have published draft genome sequences. Since all have humans as the definitive host, standard avenues of research that rely on culturing and genetics have often not been possible. Therefore, genome sequencing provides an important window into understanding the biology of these parasites. The need for large amounts of high quality genomic DNA from homozygous, inbred lines; the availability of only short sequence reads from next-generation sequencing platforms at a reasonable expense; and the lack of random large insert libraries has limited our ability to generate high quality genome sequences for these parasites. However, the Pacific Biosciences single molecule, real-time sequencing platform holds great promise in reducing input amounts and generating sufficiently long sequences that bypass the need for large insert paired libraries. Here, we report on efforts to generate a more complete genome assembly for L. loa using genetically heterogeneous DNA isolated from a single clinical sample and sequenced on the Pacific Biosciences platform. To obtain the best assembly, numerous assemblers and sequencing datasets were analyzed, combined, and compared. Quiver-informed trimming of an assembly of only Pacific Biosciences reads by HGAP2 was selected as the final assembly of 96.4 Mbp in 2,250 contigs. This results in ~9% more of the genome in ~85% fewer contigs from ~80% less starting material at a fraction of the cost of previous Roche 454-based sequencing efforts. The result is the most complete filarial nematode assembly produced thus far and demonstrates the utility of single molecule sequencing on the Pacific Biosciences platform for genetically heterogeneous metazoan genomes.


The case for early use of rapid whole-genome sequencing in management of critically ill infants: late diagnosis of Coffin-Siris syndrome in an infant with left congenital diaphragmatic hernia, congenital heart disease, and recurrent infections.
Congenital diaphragmatic hernia (CDH) results from incomplete formation of the diaphragm leading to herniation of abdominal organs into the thoracic cavity. CDH is associated with pulmonary hypoplasia, congenital heart disease, and pulmonary hypertension. Genetically, it is associated with aneuploidies, chromosomal copy-number variants, and single gene mutations. CDH is the most expensive noncardiac congenital defect. Management frequently requires implementation of extracorporeal membrane oxygenation (ECMO), which increases management expenditures 2.4-3.5-fold. The cost of management of CDH has been estimated to exceed $250 million per year. Despite in-hospital survival of 80%-90%, current management is imperfect, as a great proportion of surviving children have long-term functional deficits. We report the case of a premature infant prenatally diagnosed with CDH and congenital heart disease, who had a protracted and complicated course in the intensive care unit with multiple surgical interventions, including postcardiac surgery ECMO, gastrostomy tube placement with Nissen fundoplication, tracheostomy for respiratory failure, recurrent infections, and developmental delay. Rapid whole-genome sequencing (rWGS) identified a de novo, likely pathogenic, c.3096_ 3100delCAAAG (p.Lys1033Argfs*32) variant in ARID1B, providing a diagnosis of Coffin-Siris syndrome. Her parents elected palliative care and she died later that day.


Transthoracic ultrasonography for the immunocompromised patient. A pilot project that introduces transthoracic ultrasonography for the follow-up of hematological patients in Romania.
In the past decade, there has been significant progress in clinical hematology with the discovery of targeted molecules and thus the achievement of both hematologic and molecular responses. Nevertheless, chemotherapy remains the treatment of choice for many types of hematological malignancies. Aggressive chemotherapy leads to immunosuppression, accompanied by a high rate of infections and an increased rate of treatment-related mortality. Invasive fungal infections as well as more common bacterial and viral infections are frequent in immunocompromised patients as they are difficult to diagnose and treat. Pleuropulmonary infections in immunocompromised patients are diagnosed using clinical examination, imaging and laboratory tests. Many laboratory tests are run for several days before a final result is given and are expensive. Computer tomography is a reliable technique, but it is encumbered by high irradiation and high cost, and can assess lesions larger than 1 cm. Transthoracic ultrasound is a modern method, used in the diagnostic algorithm of pleuropulmonary pathology. It allows the diagnosis of small lesions, can be performed at the patients' bedside, with acceptable costs and no irradiation. A fast, informed and accurate medical decision is essential for a favorable outcome in immunosuppressed patients with an adjacent infection. In the current case series we present the implementation of a new protocol for the follow-up of immunocompromised patients using transthoracic ultrasonography, of great potential use in the clinic.


Interferon Alpha Induces Sustained Changes in NK Cell Responsiveness to Hepatitis B Viral Load Suppression In Vivo.
NK cells are important antiviral effectors, highly enriched in the liver, with the potential to regulate immunopathogenesis in persistent viral infections. Here we examined whether changes in the NK pool are induced when patients with eAg-positive CHB are 'primed' with PegIFNα and importantly, whether these changes are sustained or further modulated long-term after switching to nucleos(t)ides (sequential NUC therapy), an approach currently tested in the clinic. Longitudinal sampling of a prospectively recruited cohort of patients with eAg+CHB showed that the cumulative expansion of CD56bright NK cells driven by 48-weeks of PegIFNα was maintained at higher than baseline levels throughout the subsequent 9 months of sequential NUCs. Unexpectedly, PegIFNα-expanded NK cells showed further augmentation in their expression of the activating NK cell receptors NKp30 and NKp46 during sequential NUCs. The expansion in proliferating, functional NK cells was more pronounced following sequential NUCs than in comparison cohorts of patients treated with de novo NUCs or PegIFNα only. Reduction in circulating HBsAg concentrations, a key goal in the path towards functional cure of CHB, was only achieved in those patients with enhancement of NK cell IFNγ and cytotoxicity but decrease in their expression of the death ligand TRAIL. In summary, we conclude that PegIFNα priming can expand a population of functional NK cells with an altered responsiveness to subsequent antiviral suppression by NUCs. Patients on sequential NUCs with a distinct NK cell profile show a decline in HBsAg, providing mechanistic insights for the further optimisation of treatment strategies to achieve sustained responses in CHB.


Nonverbal generics: human infants interpret objects as symbols of object kinds.
Human infants are involved in communicative interactions with others well before they start to speak or understand language. It is generally thought that this communication is useful for establishing interpersonal relations and supporting joint activities, but, in the absence of symbolic functions that language provides, these early communicative contexts do not allow infants to learn about the world. However, recent studies suggest that when someone demonstrates something using an object as the medium of instruction, infants can conceive the object as an exemplar of the whole class of objects of the same kind. Thus, an object, just like a word, can play the role of a symbol that stands for something else than itself, and infants can learn general knowledge about a kind of object from nonverbal communication about a single item of that kind. This rudimentary symbolic capacity may be one of the roots of the development of symbolic understanding in children.


Carbonylation of adipose proteins in obesity and insulin resistance: identification of adipocyte fatty acid-binding protein as a cellular target of 4-hydroxynonenal.
Obesity is a state of mild inflammation correlated with increased oxidative stress. In general, pro-oxidative conditions lead to production of reactive aldehydes such as trans-4-hydroxy-2-nonenal (4-HNE) and trans-4-oxo-2-nonenal implicated in the development of a variety of metabolic diseases. To investigate protein modification by 4-HNE as a consequence of obesity and its potential relationship to the development of insulin resistance, proteomics technologies were utilized to identify aldehyde-modified proteins in adipose tissue. Adipose proteins from lean insulin-sensitive and obese insulin-resistant C57Bl/6J mice were incubated with biotin hydrazide and detected using horseradish peroxidase-conjugated streptavidin. High carbohydrate, high fat feeding of mice resulted in a approximately 2-3-fold increase in total adipose protein carbonylation. Consistent with an increase in oxidative stress in obesity, the abundance of glutathione S-transferase A4 (GSTA4), a key enzyme responsible for metabolizing 4-HNE, was decreased approximately 3-4-fold in adipose tissue of obese mice. To identify specific carbonylated proteins, biotin hydrazide-modified adipose proteins from obese mice were captured using avidin-Sepharose affinity chromatography, proteolytically digested, and subjected to LC-ESI MS/MS. Interestingly enzymes involved in cellular stress response, lipotoxicity, and insulin signaling such as glutathione S-transferase M1, peroxiredoxin 1, glutathione peroxidase 1, eukaryotic elongation factor 1alpha-1 (eEF1alpha1), and filamin A were identified. The adipocyte fatty acid-binding protein, a protein implicated in the regulation of insulin resistance, was found to be carbonylated in vivo with 4-HNE. In vitro modification of adipocyte fatty acid-binding protein with 4-HNE was mapped to Cys-117, occurred equivalently using either the R or S enantiomer of 4-HNE, and reduced the affinity of the protein for fatty acids approximately 10-fold. These results indicate that obesity is accompanied by an increase in the carbonylation of a number of adipose-regulatory proteins that may serve as a mechanistic link between increased oxidative stress and the development of insulin resistance.


AlphaS1-casein, which is essential for efficient ER-to-Golgi casein transport, is also present in a tightly membrane-associated form.
Caseins, the main milk proteins, aggregate in the secretory pathway of mammary epithelial cells into large supramolecular structures, casein micelles. The role of individual caseins in this process and the mesostructure of the casein micelle are poorly known. In this study, we investigate primary steps of casein micelle formation in rough endoplasmic reticulum-derived vesicles prepared from rat or goat mammary tissues. The majority of both alphaS1- and beta-casein which are cysteine-containing casein was dimeric in the endoplasmic reticulum. Saponin permeabilisation of microsomal membranes in physico-chemical conditions believed to conserve casein interactions demonstrated that rat immature beta-casein is weakly aggregated in the endoplasmic reticulum. In striking contrast, a large proportion of immature alphaS1-casein was recovered in permeabilised microsomes when incubated in conservative conditions. Furthermore, a substantial amount of alphaS1-casein remained associated with microsomal or post-ER membranes after saponin permeabilisation in non-conservative conditions or carbonate extraction at pH11, all in the presence of DTT. Finally, we show that protein dimerisation via disulfide bond is involved in the interaction of alphaS1-casein with membranes. These experiments reveal for the first time the existence of a membrane-associated form of alphaS1-casein in the endoplasmic reticulum and in more distal compartments of the secretory pathway of mammary epithelial cells. Our data suggest that alphaS1-casein, which is required for efficient export of the other caseins from the endoplasmic reticulum, plays a key role in early steps of casein micelle biogenesis and casein transport in the secretory pathway.


Abscisic acid: biosynthesis, inactivation, homoeostasis and signalling.
The phytohormone abscisic acid (ABA) plays crucial roles in numerous physiological processes during plant growth and abiotic stress responses. The endogenous ABA level is controlled by complex regulatory mechanisms involving biosynthesis, catabolism, transport and signal transduction pathways. This complex regulatory network may target multiple levels, including transcription, translation and post-translational regulation of genes involved in ABA responses. Most of the genes involved in ABA biosynthesis, catabolism and transport have been characterized. The local ABA concentration is critical for initiating ABA-mediated signalling during plant development and in response to environmental changes. In this chapter we discuss the mechanisms that regulate ABA biosynthesis, catabolism, transport and homoeostasis. We also present the findings of recent research on ABA perception by cellular receptors, and ABA signalling in response to cellular and environmental conditions.


A novel electronic data collection system for large-scale surveys of neglected tropical diseases.
Large cross-sectional household surveys are common for measuring indicators of neglected tropical disease control programs. As an alternative to standard paper-based data collection, we utilized novel paperless technology to collect data electronically from over 12,000 households in Ethiopia. We conducted a needs assessment to design an Android-based electronic data collection and management system. We then evaluated the system by reporting results of a pilot trial and from comparisons of two, large-scale surveys; one with traditional paper questionnaires and the other with tablet computers, including accuracy, person-time days, and costs incurred. The electronic data collection system met core functions in household surveys and overcame constraints identified in the needs assessment. Pilot data recorders took 264 (standard deviation (SD) 152 sec) and 260 sec (SD 122 sec) per person registered to complete household surveys using paper and tablets, respectively (P = 0.77). Data recorders felt a lack of connection with the interviewee during the first days using electronic devices, but preferred to collect data electronically in future surveys. Electronic data collection saved time by giving results immediately, obviating the need for double data entry and cross-correcting. The proportion of identified data entry errors in disease classification did not differ between the two data collection methods. Geographic coordinates collected using the tablets were more accurate than coordinates transcribed on a paper form. Costs of the equipment required for electronic data collection was approximately the same cost incurred for data entry of questionnaires, whereas repeated use of the electronic equipment may increase cost savings. Conducting a needs assessment and pilot testing allowed the design to specifically match the functionality required for surveys. Electronic data collection using an Android-based technology was suitable for a large-scale health survey, saved time, provided more accurate geo-coordinates, and was preferred by recorders over standard paper-based questionnaires.


A Doppler ultrasonographic study of cyclic changes of ovarian perfusion in the Beagle bitch.
Changes in intraovarian arterial blood flow were monitored by means of colour-coded and pulsed Doppler ultrasonography in Beagle bitches during the normal oestrous cycle (n = 11) and pregnancy (n = 3), and at PGF(2alpha)-induced luteolysis (n = 4). The ultrasonographic findings were related to the reproductive stage of the bitch, as determined by vaginoscopical and cytological criteria, and by the concentrations of oestradiol, LH and progesterone in peripheral blood plasma. Colour-coded Doppler ultrasonography was used to visualize and estimate intraovarian vascularization, and pulsed Doppler ultrasonography was used to measure the arterial blood flow. The systolic and diastolic peak velocities, the end-diastolic velocity, and the pulsatility index and resistance index were calculated for quantitative analysis of the Doppler waveforms. Intraovarian perfusion increased gradually during pro-oestrus. A marked enhancement of intraovarian colouring and blood flow velocities, and a decline in the indices for pulsatility and resistance were observed in the preovulatory period. Maximum perfusion was observed at ovulation and during the early luteal phase. Significant differences (P < 0.05) were detected for the values of all calculated Doppler parameters 2 days before and 2 days after ovulation. Intraovarian blood flow decreased gradually in accordance with luteal regression. Treatment with PGF(2alpha) caused a distinct decline in luteal activity and a concomitant reduction in intraovarian perfusion. The values of blood flow parameters found during the luteal phase of pregnant bitches were comparable to those of the normocyclic bitches. Doppler ultrasonography of the intraovarian arteries in bitches provides complementary information about cyclic changes of ovarian function.


A longitudinal daily diary analysis of condom use during bleeding-associated vaginal sex among adolescent females.
Sex during bleeding is a risk factor for sexually transmitted infection (STI) and other bloodborne viruses, including HIV. We examined daily predictors of adolescent women's male condom use during bleeding-associated vaginal sex. Adolescent females (N=387; 14-17 years) were recruited from primary care clinics for a longitudinal cohort study of STIs and sexual behaviour. Data were daily partner-specific sexual diaries; generalised estimating equation logistic regression assessed the likelihood of condom use during bleeding-associated vaginal sex. Less than 30% of bleeding-associated vaginal sex events were condom protected. Condom use during these events was less likely with younger age, higher partner support, higher partner negativity or past week bleeding-associated sex with a given partner; condom use was more likely with high individual mood and past week condom use during bleeding-associated vaginal sex with a given partner. Low condom rates during bleeding-associated vaginal sex can increase STI and bloodborne virus risk. Providers should consider integrating partner-specific and behavioural factors when they deliver sexual health messages to young women.


Management of community-acquired pneumonia in the era of pneumococcal resistance: a report from the Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group.
To provide recommendations for the management of community-acquired pneumonia and the surveillance of drug-resistant Streptococcus pneumoniae (DRSP). We addressed the following questions: (1) Should pneumococcal resistance to beta-lactam antimicrobial agents influence pneumonia treatment? (2) What are suitable empirical antimicrobial regimens for outpatient treatment of community-acquired pneumonia in the DRSP era? (3) What are suitable empirical antimicrobial regimens for treatment of hospitalized patients with community-acquired pneumonia in the DRSP era? and (4) How should clinical laboratories report antibiotic susceptibility patterns for S pneumoniae, and what drugs should be included in surveillance if community-acquired pneumonia is the syndrome of interest? Experts in the management of pneumonia and the DRSP Therapeutic Working Group, which includes clinicians, academicians, and public health practitioners, met at the Centers for Disease Control and Prevention in March 1998 to discuss the management of pneumonia in the era of DRSP. Published and unpublished data were summarized from the scientific literature and experience of participants. After group presentations and review of background materials, subgroup chairs prepared draft responses, which were discussed as a group. When implicated in cases of pneumonia, S pneumoniae should be considered susceptible if penicillin minimum inhibitory concentration (MIC) is no greater than 1 microg/mL, of intermediate susceptibility if MIC is 2 microg/ mL, and resistant if MIC is no less than 4 microg/mL. For outpatient treatment of community-acquired pneumonia, suitable empirical oral antimicrobial agents include a macrolide (eg, erythromycin, clarithromycin, azithromycin), doxycycline (or tetracycline) for children aged 8 years or older, or an oral beta-lactam with good activity against pneumococci (eg, cefuroxime axetil, amoxicillin, or a combination of amoxicillin and clavulanate potassium). Suitable empirical antimicrobial regimens for inpatient pneumonia include an intravenous beta-lactam, such as cefuroxime, ceftriaxone sodium, cefotaxime sodium, or a combination of ampicillin sodium and sulbactam sodium plus a macrolide. New fluoroquinolones with improved activity against S pneumoniae can also be used to treat adults with community-acquired pneumonia. To limit the emergence of fluoroquinolone-resistant strains, the new fluoroquinolones should be limited to adults (1) for whom one of the above regimens has already failed, (2) who are allergic to alternative agents, or (3) who have a documented infection with highly drug-resistant pneumococci (eg, penicillin MIC > or =4 microg/mL). Vancomycin hydrochloride is not routinely indicated for the treatment of community-acquired pneumonia or pneumonia caused by DRSP.


Anaylsis of ventricular activation and repolarization from intramural and epicardial potential distributions for ectopic beats in the intact dog.
Ventricular activation and repolarization were examined by measuring intramural and epicardial potential distributions during ectopic sequences in intact dogs. Potential distributions were used because they provided a direct measure of all of repolarization. Ectopic sequences produced almost unidirectional excitation across the heart along with repolarization events that were different from normal. During ectopic repolarization, positive potentials occurred over a broad area surrounding the ectopic focus, and negative potentials occurred over a large area on the opposite side of the heart where excitation terminated. The potentials in the walls of both ventricles were more positive in the outer layers and more negative in the inner layers, a gradient similar to normal. A maximum initially was at the ectopic site with a magnitude greater than that of the minimum, but the maximum subsequently decreased in magnitude and shifted toward the minimum while the minimum increased in magnitude. The steepest gradients were initially around the maximum, and they then shifted toward the minimum. The results show that ventricular repolatization potential distributions during ectopic beats are predominantly influenced by gradients from one side of the heart to the other (transventricular gradients) in contrast to normal repolatization distributions which are predominantly influenced by gradients across the wall (transmural gradients).


Immersion depth of surfactants at the free water surface: a computer simulation and ITIM analysis study.
The adsorption layer of five different surfactants, namely, pentanol, octanol, dodecanol, dodecyl trimethyl ammonium chloride, and sodium dodecyl sulfate, has been analyzed on the basis of molecular dynamics simulation results at two surface densities, namely, 1 and 4 μmol/m(2). The analyses have primarily focused on the question of how deeply, in terms of atomistic layers, the different surfactant molecules are immersed into the aqueous phase. The orientation and conformation of the surfactant molecules have also been analyzed. The obtained results reveal a clear difference between the immersion behavior of the alcoholic and ionic surfactants. Thus, alcoholic surfactants are found to be located right at the water surface, their apolar tails not being considerably immersed into the aqueous phase and the alcoholic headgroups being preferentially located in the surface layer of water. Ionic surfactants are immersed several layers deep into the aqueous phase, with headgroup atoms reaching the sixth-eighth and tail carbon atoms reaching the third-fourth subsurface layer in several cases. The observed difference is related, on the one hand, to the ability of the alcoholic surfactants of substituting surface water molecules in their lateral hydrogen bonding network at the water surface and that of their apolar tails for replacing dangling hydrogens and, on the other hand, to the energetic gain of the ionic headgroups if they are fully hydrated rather than being in contact with hydrocarbon tail groups.


Rabbit-specific computational modelling of ventricular cell electrophysiology: Using populations of models to explore variability in the response to ischemia.
Computational modelling, combined with experimental investigations, is a powerful method for investigating complex cardiac electrophysiological behaviour. The use of rabbit-specific models, due to the similarities of cardiac electrophysiology in this species with human, is especially prevalent. In this paper, we first briefly review rabbit-specific computational modelling of ventricular cell electrophysiology, multi-cellular simulations including cellular heterogeneity, and acute ischemia. This mini-review is followed by an original computational investigation of variability in the electrophysiological response of two experimentally-calibrated populations of rabbit-specific ventricular myocyte action potential models to acute ischemia. We performed a systematic exploration of the response of the model populations to varying degrees of ischemia and individual ischemic parameters, to investigate their individual and combined effects on action potential duration and refractoriness. This revealed complex interactions between model population variability and ischemic factors, which combined to enhance variability during ischemia. This represents an important step towards an improved understanding of the role that physiological variability may play in electrophysiological alterations during acute ischemia.


Cannabis for pain in orthopedics: a systematic review focusing on study methodology
Medical cannabis use is an emerging topic of interest in orthopedics. Although there is a large amount of literature on medical cannabis use for managing various types of pain, few studies have focused on orthopedic conditions. There is little high-quality evidence in core orthopedic areas. The objective of this study was to summarize the literature on the efficacy of cannabis use for pain related to orthopedic conditions. We conducted a systematic review of the literature on the use of cannabinoids for pain management in core orthopedic conditions. Two independent reviewers extracted information on reporting quality, risk of bias, drugs, population, control, duration of study, pain outcomes and the authors' conclusions regarding efficacy for pain outcomes. We identified 33 orthopedic studies, including 21 primary studies and 12 reviews. Study quality was generally low to moderate. Six of the included studies had a control group and 15 were noncontrolled studies. Methodologies, drugs and protocols of administration varied greatly across studies. Study conclusions were generally positive in noncontrolled studies and mixed in controlled studies. Studies using higher doses tended to conclude that cannabis use was effective, but the potential for harmful effects may also be increased with higher doses. Variability in the methodologies used in cannabis research makes it challenging to draw conclusions about dosing, routes and frequency of administration. Most of the existing evidence suggests that medical cannabis use is effective, but this efficacy has been demonstrated only when either there is no comparator or cannabis is compared with placebo. Studies using an active comparator have not demonstrated efficacy. Future research should focus on improving study reporting and methodologic quality so that protocols that optimize pain control while minimizing harmful effects can be determined.


Molecular phylogenetic reconstruction of the endemic Asian salamander family Hynobiidae (Amphibia, Caudata).
The salamander family Hynobiidae contains over 50 species and has been the subject of a number of molecular phylogenetic investigations aimed at reconstructing branches across the entire family. In general, studies using the greatest amount of sequence data have used reduced taxon sampling, while the study with the greatest taxon sampling has used a limited sequence data set. Here, we provide insights into the phylogenetic history of the Hynobiidae using both dense taxon sampling and a large mitochondrial DNA sequence data set. We report exclusive new mitochondrial DNA data of 2566 aligned bases (with 151 excluded sites, of included sites 1157 are variable with 957 parsimony informative). This is sampled from two genic regions encoding a 12S-16S region (the 3' end of 12S rRNA, tRNA(VAI), and the 5' end of 16S rRNA), and a ND2-COI region (ND2, tRNA(Trp), tRNA(Ala), tRNA(Asn), the origin for light strand replication--O(L), tRNA(Cys), tRNAT(Tyr), and the 5' end of COI). Analyses using parsimony, Bayesian, and maximum likelihood optimality criteria produce similar phylogenetic trees, with discordant branches generally receiving low levels of branch support. Monophyly of the Hynobiidae is strongly supported across all analyses, as is the sister relationship and deep divergence between the genus Onychodactylus with all remaining hynobiids. Within this latter grouping our phylogenetic results identify six clades that are relatively divergent from one another, but for which there is minimal support for their phylogenetic placement. This includes the genus Batrachuperus, the genus Hynobius, the genus Pachyhynobius, the genus Salamandrella, a clade containing the genera Ranodon and Paradactylodon, and a clade containing the genera Liua and Pseudohynobius. This latter clade receives low bootstrap support in the parsimony analysis, but is consistent across all three analytical methods. Our results also clarify a number of well-supported relationships within the larger Batrachuperus and Hynobius clades. While the relationships identified in this study do much to clarify the phylogenetic history of the Hynobiidae, the poor resolution among major hynobiid clades, and the contrast of mtDNA-derived relationships with recent phylogenetic results from a small number of nuclear genes, highlights the need for continued phylogenetic study with larger numbers of nuclear loci.


ESTIMATING A DOSE-RESPONSE RELATIONSHIP BETWEEN LENGTH OF STAY AND FUTURE RECIDIVISM IN SERIOUS JUVENILE OFFENDERS.
The effect of sanctions on subsequent criminal activity is of central theoretical importance in criminology. A key question for juvenile justice policy is the degree to which serious juvenile offenders respond to sanctions and/or treatment administered by the juvenile court. The policy question germane to this debate is finding the level of confinement within the juvenile justice system that maximizes the public safety and therapeutic benefits of institutional confinement. Unfortunately, research on this issue has been limited with regard to serious juvenile offenders. We use longitudinal data from a large sample of serious juvenile offenders from two large cities to 1) estimate a causal treatment effect of institutional placement, as opposed to probation, on future rate of rearrest and 2) investigate the existence of a marginal effect (i.e., benefit) for longer length of stay once the institutional placement decision had been made. We accomplish the latter by determining a dose-response relationship between the length of stay and future rates of rearrest and self-reported offending. The results suggest that an overall null effect of placement exists on future rates of rearrest or self-reported offending for serious juvenile offenders. We also find that, for the group placed out of the community, it is apparent that little or no marginal benefit exists for longer lengths of stay. Theoretical, empirical, and policy issues are outlined.


Enhanced absorptive characteristics of metal nanoparticle-coated silicon nanowires for solar cell applications.
The optical properties of metal nanoparticle (NP)-coated silicon nanowires (Si NWs) are theoretically investigated using COMSOL Multiphysics commercial software. A geometrical array of periodic Si NWs coated with metal NPs is proposed. The simulation demonstrates that light absorption could be enhanced significantly in a long wavelength region of the solar spectrum, based upon the localized surface plasmons generated around metal NPs. Various metal NPs, such as Au, Ag, and Al, are all found to increase their light absorption while in contact with Si NWs, in which the Au NPs show the best result in light enhancement. This theoretical work might prove useful in providing a fundamental understanding toward improving further the efficiency of Si wired solar cells.


Improving Color Constancy in an Ambient Light Environment Using the Phong Reflection Model.
We present a physics-based illumination estimation approach explicitly designed to handle natural images under ambient light. Existing physics-based color constancy methods are theoretically perfect but do not handle real-world images well because the majority of these methods assume a single illuminant. Therefore, specular pixels selected using existing methods produce estimated dichromatic lines that are thick or curvilinear in the presence of ambient light, thus generating significant errors. Based on the Phong reflection model, we show that a group of specular pixels on a uniformly colored object, although they are subject to intensity thresholding, produce a unique dichromatic line length depending on the geometry of each image path. Assuming that the longest dichromatic line is the most desirable when estimating the chromaticity of an illuminant, ambient-robust specular pixels are also found on the same path on which the longest dichromatic line segment is generated. Therefore, we propose a method to find the optimal image path in which the specular pixels produce the longest dichromatic line. Even though the number of collected specular pixels is reduced using the proposed method, they are proven to be more accurate when determining the illuminant chromaticity even in the existing methods. Experiments with an established benchmark data set and a self-produced image set find that the proposed method is better able to locate the illuminant chromaticity compared with the state-of-the-art color constancy methods.


Critical depurinating DNA adducts: Estrogen adducts in the etiology and prevention of cancer and dopamine adducts in the etiology and prevention of Parkinson's disease.
Endogenous estrogens become carcinogens when dangerous metabolites, the catechol estrogen quinones, are formed. In particular, the catechol estrogen-3,4-quinones can react with DNA to produce an excess of specific depurinating estrogen-DNA adducts. Loss of these adducts leaves apurinic sites in the DNA, generating subsequent cancer-initiating mutations. Unbalanced estrogen metabolism yields excessive catechol estrogen-3,4-quinones, increasing formation of depurinating estrogen-DNA adducts and the risk of initiating cancer. Evidence for this mechanism of cancer initiation comes from various types of studies. High levels of depurinating estrogen-DNA adducts have been observed in women with breast, ovarian or thyroid cancer, as well as in men with prostate cancer or non-Hodgkin lymphoma. Observation of high levels of depurinating estrogen-DNA adducts in high risk women before the presence of breast cancer indicates that adduct formation is a critical factor in breast cancer initiation. Formation of analogous depurinating dopamine-DNA adducts is hypothesized to initiate Parkinson's disease by affecting dopaminergic neurons. Two dietary supplements, N-acetylcysteine and resveratrol complement each other in reducing formation of catechol estrogen-3,4-quinones and inhibiting formation of estrogen-DNA adducts in cultured human and mouse breast epithelial cells. They also inhibit malignant transformation of these cells. In addition, formation of adducts was reduced in women who followed a Healthy Breast Protocol that includes N-acetylcysteine and resveratrol. When initiation of cancer is blocked, promotion, progression and development of the disease cannot occur. These results suggest that reducing formation of depurinating estrogen-DNA adducts can reduce the risk of developing a variety of types of human cancer.


Expression of phosphatidylinositol 3-kinase during EGF-stimulated wound repair in rabbit corneal epithelium.
To investigate the effect of epidermal growth factor (EGF) on the induction of phosphatidylinositol 3-kinase (PI 3- kinase) gene expression during rabbit corneal epithelial wound repair. Epithelial wounds (6 mm in size) were created in rabbit corneas and EGF (2 microg) applied every 8 hours to one eye, and the other eye served as a control. The wound repair was monitored by staining the tissue with fluorescein followed by photography. The wound area was quantified with a computer program. At different time intervals, the rabbits were killed and the corneal epithelium used for estimation of PI 3-kinase activity, western blot analysis, or reverse transcription-polymerase chain reaction (RT-PCR). For in situ hybridization, the whole corneas were sectioned and the sections processed with PI 3-kinase mRNA probes. In the untreated eye, the epithelial wound progressively healed in a time-dependent manner, with 75% of the wound closed at 48 hours post wounding. Application of EGF to the corneal epithelium further stimulated wound repair at all time intervals, and the wound was completely closed at 48 hours. Analysis of PI 3-kinase showed a time-dependent increase in its enzyme activity that was maximally increased at 36 hours, the time when the wound was nearly closed. Western blot analysis revealed increased amounts of PI 3- kinase protein during the course of wound repair. Analysis of RT-PCR products from epithelial tissues, taken at different times during wound repair, showed increased PI 3-kinase expression that was maximum at 48 hours post wounding. A visible increase in PI 3-kinase gene expression was also detected by in situ hybridization during the course of the wound repair. This expression was increased maximally by EGF at 48 hours post wounding. The results indicate a temporal correlation between increased activation and expression of PI 3- kinase and the epithelial wound repair. Topical application of EGF further stimulates the activity and expression of PI 3- kinase. It is suggested that PI 3- kinase and its products may play a role in EGF-induced cell proliferation during corneal epithelial wound repair.


Remote monitoring technologies in Alzheimer's disease: design of the RADAR-AD study.
Functional decline in Alzheimer's disease (AD) is typically measured using single-time point subjective rating scales, which rely on direct observation or (caregiver) recall. Remote monitoring technologies (RMTs), such as smartphone applications, wearables, and home-based sensors, can change these periodic subjective assessments to more frequent, or even continuous, objective monitoring. The aim of the RADAR-AD study is to assess the accuracy and validity of RMTs in measuring functional decline in a real-world environment across preclinical-to-moderate stages of AD compared to standard clinical rating scales. This study includes three tiers. For the main study, we will include participants (n = 220) with preclinical AD, prodromal AD, mild-to-moderate AD, and healthy controls, classified by MMSE and CDR score, from clinical sites equally distributed over 13 European countries. Participants will undergo extensive neuropsychological testing and physical examination. The RMT assessments, performed over an 8-week period, include walk tests, financial management tasks, an augmented reality game, two activity trackers, and two smartphone applications installed on the participants' phone. In the first sub-study, fixed sensors will be installed in the homes of a representative sub-sample of 40 participants. In the second sub-study, 10 participants will stay in a smart home for 1 week. The primary outcome of this study is the difference in functional domain profiles assessed using RMTs between the four study groups. The four participant groups will be compared for each RMT outcome measure separately. Each RMT outcome will be compared to a standard clinical test which measures the same functional or cognitive domain. Finally, multivariate prediction models will be developed. Data collection and privacy are important aspects of the project, which will be managed using the RADAR-base data platform running on specifically designed biomedical research computing infrastructure. First results are expected to be disseminated in 2022. Our study is well placed to evaluate the clinical utility of RMT assessments. Leveraging modern-day technology may deliver new and improved methods for accurately monitoring functional decline in all stages of AD. It is greatly anticipated that these methods could lead to objective and real-life functional endpoints with increased sensitivity to pharmacological agent signal detection.


Synergistic effects of Y2 and Y4 receptors on adiposity and bone mass revealed in double knockout mice.
Neuropeptide Y regulates numerous physiological processes via at least five different Y receptors, but the specific roles of each receptor are still unclear. We previously demonstrated that Y2 receptor knockout results in a lean phenotype, increased cancellous bone volume, and an increase in plasma pancreatic polypeptide (PP), a ligand for Y4 receptors. PP-overexpressing mice are also known to have a lean phenotype. Deletion of the Y4 receptor also produced a lean phenotype and increased plasma PP levels. We therefore hypothesized that part of the Y2 phenotype results from increased PP action on Y4 receptors and tested this in PP transgenic Y4(-/-) and Y2(-/-) Y4(-/-) double knockout mice. Bone mass was not altered in Y4 knockout mice. Surprisingly, despite significant hyperphagia, Y2(-/-) Y4(-/-) mice retained a markedly lean phenotype, with reduced body weight, white adipose tissue mass, leptinemia, and insulinemia. Furthermore, bone volume was also increased threefold in Y2(-/-) Y4(-/-) mice, and this was associated with enhanced osteoblastic activity. These changes were more pronounced than those observed in Y2(-/-) mice, suggesting synergy between Y2 and Y4 receptor pathways. The lack of bone changes in PP transgenic mice suggests that PP alone is not responsible for the bone mass increases but might play a major role in the lean phenotype. However, a synergistic interaction between Y2 and Y4 pathways seems to regulate bone volume and adiposity and could have important implications for possible interventions in obesity and for anabolic treatment of osteoporotic bone loss.


HYAL1-v1, an alternatively spliced variant of HYAL1 hyaluronidase: a negative regulator of bladder cancer.
Tumor cells express HYAL1 hyaluronidase, which degrades hyaluronic acid. HYAL1 expression in bladder cancer cells promotes tumor growth, invasion, and angiogenesis. We previously described five alternatively spliced variants of HYAL1 that encode enzymatically inactive proteins. The HYAL1-v1 variant lacks a 30-amino acid sequence that is present in HYAL1. In this study, we examined whether HYAL1-v1 expression affects bladder cancer growth and invasion by stably transfecting HT1376 bladder cancer cells with a HYAL1-v1 cDNA construct. Although HYAL1-v1 transfectants expressed equivalent levels of enzymatically active HYAL1 protein when compared with vector transfectants, their conditioned medium had 4-fold less hyaluronidase activity due to a noncovalent complex formed between HYAL1 and HYAL1-v1 proteins. HYAL1-v1 transfectants grew 3- to 4-fold slower due to cell cycle arrest in the G(2)-M phase and increased apoptosis. In HYAL1-v1 transfectants, cyclin B1, cdc2/p34, and cdc25c levels were > or =2-fold lower than those in vector transfectants. The increased apoptosis in HYAL1-v1 transfectants was due to the extrinsic pathway involving Fas and Fas-associated death domain up-regulation, caspase-8 activation, and BID cleavage, leading to caspase-9 and caspase-3 activation and poly(ADP-ribose) polymerase cleavage. When implanted in athymic mice, HYAL1-v1-expressing tumors grew 3- to 4-fold slower and tumor weights at day 35 were 3- to 6-fold less than the vector tumors (P < 0.001). Whereas vector tumors were infiltrating and had high mitoses and microvessel density, HYAL1-v1 tumors were necrotic, infiltrated with neutrophils, and showed low mitoses and microvessel density. Therefore, HYAL-v1 expression may negatively regulate bladder tumor growth, infiltration, and angiogenesis.


Early integration of palliative care into oncology: evidence, challenges and barriers.
Palliative care has proven to be an important component during the care of seriously ill oncology patients. In the past decade, early integration of both specialties demonstrated benefits in improving patient symptoms and pain, facilitating advance directive planning and reducing medical cost. Newer evidence also suggests it can prolong life. Several different integration models have been studied and all appear to work. Yet, palliative care is underused, and there are still many challenges and barriers preventing us from delivering the best care to our patients. In this review, we will summarize the available data from multiple randomized clinical trials, encountered challenges, and potential strategies to overcome them.


Models of care in nursing: a systematic review.
This review investigated the effect of the various models of nursing care delivery using the diverse levels of nurses on patient and nursing outcomes. All published studies that investigated patient and nursing outcomes were considered. Studies were included if the nursing delivery models only included nurses with varying skill levels. A literature search was performed using the following databases: Medline (1985-2011), CINAHL (1985-2011), EMBASE (1985 to current) and the Cochrane Controlled Studies Register (Issue 3, 2011 of Cochrane Library). In addition, the reference lists of relevant studies and conference proceedings were also scrutinised. Two reviewers independently assessed the eligibility of the studies for inclusion in the review, the methodological quality and extracted details of eligible studies. Data were analysed using the RevMan software (Nordic Cochrane Centre, Copenhagen, Denmark). Fourteen studies were included in this review. The results reveal that implementation of the team nursing model of care resulted in significantly decreased incidence of medication errors and adverse intravenous outcomes, as well as lower pain scores among patients; however, there was no effect of this model of care on the incidence of falls. Wards that used a hybrid model demonstrated significant improvement in quality of patient care, but no difference in incidence of pressure areas or infection rates. There were no significant differences in nursing outcomes relating to role clarity, job satisfaction and nurse absenteeism rates between any of the models of care. Based on the available evidence, a predominance of team nursing within the comparisons is suggestive of its popularity. Patient outcomes, nurse satisfaction, absenteeism and role clarity/confusion did not differ across model comparisons. Little benefit was found within primary nursing comparisons and the cost effectiveness of team nursing over other models remains debatable. Nonetheless, team nursing does present a better model for inexperienced staff to develop, a key aspect in units where skill mix or experience is diverse.


Validating the youth sport enjoyment construct in high school physical education.
The present study was undertaken to develop and validate a questionnaire measuring teaching processes related to physical education (PE) enjoyment. Scanlan and Lewthwaite's (1986) youth sport enjoyment model provided the theoretical foundation for this work. Content validity and item readability of the instrument were established by obtaining feedback from eight experts in psychology and four highly experienced secondary school teachers. Construct validity was then established by conducting exploratory and confirmatory factor analyses on data from 304 secondary school students (grades 8, 9, and 10). As a result of these analyses, six teaching processes related to PE enjoyment were identified: self-referent competency (four items), other-referent competency (four items), teacher-generated excitement (three items), activity-generated excitement (five items), peer interaction (two items), and parental encouragement (two items). Correlation analyses revealed that all of these processes were positively correlated with PE enjoyment. The weakest correlation was between peer interaction and enjoyment (r = .31, p < .05), and the strongest was between activity-generated excitement and enjoyment (r = .83, p < .05). We believe that the instrument is appropriate for studying affective outcomes within physical educational settings among students in grades 8, 9, and 10.


From the Cover: Arsenic Induces Accumulation of α-Synuclein: Implications for Synucleinopathies and Neurodegeneration.
Synucleinopathies, including Parkinson's disease (PD), are neurodegenerative diseases characterized by accumulation of α-synuclein (SYN), a small neuronal protein with prion like properties that plays a central role in PD pathogenesis. SYN can misfold and generate toxic oligomers/aggregates, which can be cytotoxic. Environmental arsenic (As)-containing pesticide use correlates with increased incidence of PD. Moreover, because As exposure can lead to inhibition of autophagic flux we hypothesize that As can facilitate the accumulation of toxic SYN oligomers/aggregates and subsequent increases in markers of autophagy. We therefore examined the role of As in the oligomerization of SYN, and the consequences thereof. Chronic exposure of SH-SY5Y cells overexpressing SYN to As caused a dose-dependent oligomerization of SYN, with concomitant increases in protein ubiquitination and expression of other stress markers (protein glutathione binding, γ-GCS, light chain 3 (LC3)-I/II, P62, and NAD(P)H dehydrogenase quinone 1), indicative of an increased proteotoxic stress. Immunocytochemical analyses revealed an accumulation of SYN, and it's colocalization with LC3, a major autophagic protein. Mice exposed to As (100 ppb) for 1 month, exhibited elevated SYN accumulation in the cortex and striatum, and elevations in protein ubiquitination and LC3-I and II levels. However, tyrosine hydroxylase (TH), an indicator of dopaminergic cell density, was upregulated in the As exposed animals. Because SYN can inhibit TH function, and As can decrease monoamine levels, As exposure possibly leads to compensatory mechanisms leading to an increase in TH expression. Our findings suggest that susceptible individuals may be at higher risk of developing synucleinopathies and/or neurodegeneration due to environmental As exposure.


Lysine 271 in the transmembrane domain of the T-cell antigen receptor beta chain is necessary for its assembly with the CD3 complex but not for alpha/beta dimerization.
The T-cell antigen receptor (TcR) complex present on most T-cells is formed by a clone-specific disulfide-linked alpha/beta heterodimer noncovalently associated to the CD3 complex, the latter composed of five invariant polypeptides: gamma, delta, epsilon, zeta/zeta, or zeta/eta. The presence of conserved, oppositely charged, amino acids in the predicted transmembrane domains of all the subunits of the TcR.CD3 complex suggests that these residues may have a critical function in the assembly and/or stabilization of the complex. In order to analyze the role of the transmembrane-charged amino acids in the association and cell surface expression of the TcR.CD3 complex, we have carried out site-directed mutagenesis of Lys271 in the transmembrane domain of the TcR beta chain and analyzed the capacity of the altered chain to assemble in a TcR beta-negative T-cell line. Here we show that substitution of this positively charged residue by alanine or glutamine does not prevent cytoplasmic association of alpha and beta chains to form disulfide-linked heterodimers, but does abolish formation of an alpha/beta.CD3 complex and, consequently, its expression on the cell surface.


The dangers of rationing dialysis treatment: the dilemma facing a developing country.
The increasing burden of chronic kidney disease places enormous strains on resources of all countries, but especially of those with emerging economies. Few developing countries are able to afford dialysis programs and those that do ration this scarce resource. In South Africa, rationing has been practiced since the introduction of dialysis. Our renal unit carefully screened patients with end-stage kidney disease (ESKD) based on certain medical and socioeconomic criteria. The outcome of these decisions taken by the Assessment Committee is reviewed in this study. Details of the 2442 patients with ESKD assessed between 1988 and 2003 for the renal replacement program were captured. Using univariate and multivariate analysis, the odds of being accepted for treatment based on several variables were determined. The majority (52.7%) of patients with ESKD were not offered renal replacement therapy in the period of study. The number of kidney transplants progressively decreased, as did the number of patients accepted. The patients mostly likely to be accepted for renal replacement therapy were aged 20-40 years, white, employed, married, non-diabetic, and lived in proximity to a dialysis center. Almost 60% of patients were denied renal replacement treatment because of social factors related to poverty. In a developing country, where rationing of treatment is unavoidable, it is difficult to ensure equity of treatment and certain groups are advantaged over others. In our experience, socioeconomic factors influenced decision to accept patients more profoundly than medical ones.


Second harmonic generation correlation spectroscopy for single molecule experiments.
We demonstrate a single molecule detection approach to further extend the detection limit of correlation spectroscopic techniques through the Second Harmonic Generation Correlation Spectroscopy (SHGCS). SHG signals with high signal-to-noise ratio (SNR) were obtained from Barium titanium oxide, BaTiO(3) (BTO) nanocrystals (NCs) upon excitation by a femto-second laser fitted to the scanning confocal bench. The fluctuation of SHG signals from BTO NCs in transparent and turbid media was examined and their diffusion time and particle concentration were evaluated by autocorrelation. Proof-of-concept measurements indicate that water-dispersed BTO NCs at different concentrations yield an average diffusion time of 6.43 ± 0.68 ms and the detection limit of SHGCS was found to be at 814 ± 41 fM, approximately 100 folds below the detection limit of fluorescence correlation spectroscopy (FCS). The dynamics of BTO NCs was demonstrated in serum with high SNR and selectivity to show its potential applicability in biomedicine. High SNR and the sub-picomolar detection limit positions SHGCS as an excellent technique for ultralow single particle or single molecule experimentation in a complex medium.


[Allogenic hematopoietic stem cell transplantation with unrelated cord blood: report of three cases from the Chilean cord blood bank].
Public cord blood banks are a source of hematopoietic stem cells for patients with hematological diseases who lack a family donor and need allogeneic transplantation. In June 2007 we started a cord blood bank with units donated in three maternity wards in Santiago, Chile. We report the first three transplants done with cord blood units form this bank. Cord blood units were obtained by intrauterine collection at delivery. They were depleted of plasma and red cells and frozen in liquid nitrogen. Tests for total nucleated cells, CD34 cell content, viral serology, bacterial cultures and HLA A, B and DRB1 were done. Six hundred cord blood units were stored by March 2012. Three patients received allogeneic transplant with cord blood from our bank, two with high risk lymphoblastic leukemia and one with severe congenital anemia. They received conditioning regimens according to their disease and usual supportive care for unrelated donor transplantation until full hematopoietic and immune reconstitution was achieved. The three patients had early engraftment of neutrophils and platelets. The child corrected his anemia and the leukemia patients remain in complete remission. The post-transplant course was complicated with Epstein Barr virus, cytomegalovirus and BK virus infection. Two patients are fully functional 24 and 33 months after transplant, the third is still receiving immunosuppression.


Investigation of triboelectric charging in dry powder inhalers using electrical low pressure impactor (ELPI).
Electrostatics and triboelectrification phenomena in dry powder inhalers (DPI) are not well understood, but as shown in this study they may play an important role. Using model formulations of albuterol in lactose, the extent of triboelectrification in the operation of DPI was investigated using an electrical low pressure impactor (ELPI). An experimental apparatus was developed, the performance of the ELPI was evaluated for consistency and reproducibility, and compared to a conventional inertial impactor. Using a statistical experimental design the effects of lactose type, drug load, capsule fill, capsule material, and inhaler were assessed. DPI formulations appear to be subject to strong triboelectric effects. Charge separation can occur between different size fractions, i.e. different fractions can carry charges of different sign. In particular, lactose type, inhaler, and capsule material have a strong effect on the magnitude and polarity of the charge developed during DPI operation. The study suggests that the polarity of the aerosol can be controlled by choice of lactose type, capsule material, and inhaler, which could be exploited for targeting different lung physiologies.


Outcome after renal transplantation. Part II: quality of life and psychosocial adjustment.
Knowledge of health-related quality of life (QOL) and psychosocial adjustment (PA) in children after renal transplantation (RTPL) is limited. QOL and PA were evaluated by standardized tests in patients after RTPL. Thirty-seven children of median age 14.5 years (range 6.5-17 years) were investigated a mean 4.5 years (range 0.5-12.8 years) after RTPL. Child- and parent-rated QOL was evaluated with the Child Quality of life Questionnaire of The Netherlands Organization for Applied Scientific Research Academical Medical Centre (TNO-AZL). PA was assessed by the Child Behaviour Checklist (CBCL) providing parental reports of a child's behaviour. In patients' self-ratings, the QOL dimension physical complaints (P < 0.0005) scored significantly better than that of healthy controls, whereas the dimension positive emotional functioning was impaired (P = 0.02). Parents rated motor functioning (P = 0.002), autonomy (P = 0.01), cognition (P = 0.04) and positive emotions (P < 0.0005) as significantly impaired. Parents also assessed PA significantly (P = 0.02) impaired with regard to internalizing behaviour. Dialysis duration, young age at RTPL, living-related donation, steroid treatment, adverse family relationships and maternal distress had a significantly negative impact on QOL and PA (P < 0.05). Patients rated QOL higher than did healthy controls. Parents evaluated their children's QOL and PA more pessimistically than did the patients themselves. Both illness-related variables and family environment played an important role.


Susceptibility to neurodegeneration in a glaucoma is modified by Bax gene dosage.
In glaucoma, harmful intraocular pressure often contributes to retinal ganglion cell death. It is not clear, however, if intraocular pressure directly insults the retinal ganglion cell axon, the soma, or both. The pathways that mediate pressure-induced retinal ganglion cell death are poorly defined, and no molecules are known to be required. DBA/2J mice deficient in the proapoptotic molecule BCL2-associated X protein (BAX) were used to investigate the roles of BAX-mediated cell death pathways in glaucoma. Both Bax+/- and Bax-/- mice were protected from retinal ganglion cell death. In contrast, axonal degeneration was not prevented in either Bax+/- or Bax-/- mice. While BAX deficiency did not prevent axonal degeneration, it did slow axonal loss. Additionally, we compared the effects of BAX deficiency on the glaucoma to its effects on retinal ganglion cell death due to two insults that are proposed to participate in glaucoma. As in the glaucoma, BAX deficiency protected retinal ganglion cells after axon injury by optic nerve crush. However, it did not protect retinal ganglion cells from N-methyl-D-aspartate (NMDA)-induced excitotoxicity. BAX is required for retinal ganglion cell death in an inherited glaucoma; however, it is not required for retinal ganglion cell axon degeneration. This indicates that distinct somal and axonal degeneration pathways are active in this glaucoma. Finally, our data support a role for optic nerve injury but not for NMDA receptor-mediated excitotoxicity in this glaucoma. These findings indicate a need to understand axon-specific degeneration pathways in glaucoma, and they suggest that distinct somal and axonal degeneration pathways may need to be targeted to save vision.