Comparison of different spectral domain OCT scanning protocols for diagnosing preperimetric glaucoma.
To compare the ability of spectral-domain optical coherence tomography (SDOCT) retinal nerve fiber layer (RNFL), optic nerve head (ONH), and macular measurements to detect preperimetric glaucomatous damage. The study included 142 eyes from 91 patients suspected of having the disease based on the appearance of the optic disc. All eyes had normal visual fields before the imaging session. Forty-eight eyes with progressive glaucomatous damage were included in the preperimetric glaucoma group. Ninety-four eyes without any evidence of progressive glaucomatous damage and followed untreated for 12.8 ± 3.6 years were used as controls. Areas under the receiver operating characteristic curves (AUC) were calculated to summarize diagnostic accuracies of the parameters. The three RNFL parameters with the largest AUCs were average RNFL thickness (0.89 ± 0.03), inferior hemisphere average thickness (0.87 ± 0.03), and inferior quadrant average thickness (0.85 ± 0.03). The three ONH parameters with the largest AUCs were vertical cup-to-disc ratio (0.74 ± 0.04), rim area (0.72 ± 0.05), and rim volume (0.72 ± 0.05). The three macular parameters with the largest AUCs were GCC average thickness (0.79 ± 0.04), GCC inferior thickness (0.79 ± 0.05), and GCC superior thickness (0.76 ± 0.05). Average RNFL thickness performed better than vertical cup-to-disc ratio (0.89 vs. 0.74; P = 0.007) and GCC average thickness (0.89 vs. 0.79; P = 0.015). SDOCT RNFL measurements performed better than ONH and macular measurements for detecting preperimetric glaucomatous damage in a cohort of glaucoma suspects. (ClinicalTrials.gov number, NCT00221897.).


Qualitative reasoning for biological network inference from systematic perturbation experiments.
The systematic perturbation of the components of a biological system has been proven among the most informative experimental setups for the identification of causal relations between the components. In this paper, we present Systematic Perturbation-Qualitative Reasoning (SPQR), a novel Qualitative Reasoning approach to automate the interpretation of the results of systematic perturbation experiments. Our method is based on a qualitative abstraction of the experimental data: for each perturbation experiment, measured values of the observed variables are modeled as lower, equal or higher than the measurements in the wild type condition, when no perturbation is applied. The algorithm exploits a set of IF-THEN rules to infer causal relations between the variables, analyzing the patterns of propagation of the perturbation signals through the biological network, and is specifically designed to minimize the rate of false positives among the inferred relations. Tested on both simulated and real perturbation data, SPQR indeed exhibits a significantly higher precision than the state of the art.


DNA-damage-induced type I interferon promotes senescence and inhibits stem cell function.
Expression of type I interferons (IFNs) can be induced by DNA-damaging agents, but the mechanisms and significance of this regulation are not completely understood. We found that the transcription factor IRF3, activated in an ATM-IKKα/β-dependent manner, stimulates cell-autonomous IFN-β expression in response to double-stranded DNA breaks. Cells and tissues with accumulating DNA damage produce endogenous IFN-β and stimulate IFN signaling in vitro and in vivo. In turn, IFN acts to amplify DNA-damage responses, activate the p53 pathway, promote senescence, and inhibit stem cell function in response to telomere shortening. Inactivation of the IFN pathway abrogates the development of diverse progeric phenotypes and extends the lifespan of Terc knockout mice. These data identify DNA-damage-response-induced IFN signaling as a critical mechanism that links accumulating DNA damage with senescence and premature aging.


Development of a hybrid distance occupational therapy program in Alaska.
There are shortages of health professionals in rural states. Correspondingly, health professions education programs often do not exist in these areas. Students from rural areas seeking health professions degrees frequently move out of state or to urban areas for education. To address the shortage of occupational therapists in Alaska, Creighton University, a private, Jesuit university partnered with the University of Alaska Anchorage, a public institution, to deliver a hybrid occupational therapy program to students residing near or in Anchorage, Alaska. Characteristics for a successful interorganizational partnership include effective communication, a common goal, mutual needs, and trust. This academic program was designed by applying these characteristics and using agreed-upon benchmarks for web-based programs as described by Phipps and Merisotis. The collaborative program demonstrates a model, which could be used between two disparate institutions to meet the challenges and needs of rural and underserved areas for access to health education programs.


The association of depression and perceived stress with beta cell function between African and Haitian Americans with and without type 2 diabetes.
Diabetes and diabetes-related complications are major causes of morbidity and mortality in the United States. Depressive symptoms and perceived stress have been identified as possible risk factors for beta cell dysfunction and diabetes. The purpose of this study was to assess associations between depression symptoms and perceived stress with beta cell function between African and Haitian Americans with and without type 2 diabetes. Informed consent and data were available for 462 participants (231 African Americans and 231 Haitian Americans) for this cross-sectional study. A demographic questionnaire developed by the Primary Investigator was used to collect information regarding age, gender, smoking, and ethnicity. Diabetes status was determined by self-report and confirmed by fasting blood glucose. Anthropometrics (weight, and height and waist circumference) and vital signs (blood pressure) were taken. Blood samples were drawn after 8 - 10 hours over-night fasting to measure lipid panel, fasting plasma glucose and serum insulin concentrations. The homeostatic model assessment, version 2 (HOMA2) computer model was used to calculate beta cell function. Depression was assessed using the Beck Depression Inventory-II (BDI-II) and stress levels were assessed using the Perceived Stress Scale (PSS). Moderate to severe depressive symptoms were more likely for persons with diabetes (p = 0.030). There were no differences in perceived stress between ethnicity and diabetes status (p = 0.283). General linear models for participants with and without type 2 diabetes using beta cell function as the dependent variable showed no association with depressive symptoms and perceived stress; however, Haitian Americans had significantly lower beta cell function than African Americans both with and without diabetes and adjusting for age, gender, waist circumference and smoking. Further research is needed to compare these risk factors in other race/ethnic groups.


The phylogeography and spatiotemporal spread of south-central skunk rabies virus.
The south-central skunk rabies virus (SCSK) is the most broadly distributed terrestrial viral lineage in North America. Skunk rabies has not been efficiently targeted by oral vaccination campaigns and represents a natural system of pathogen invasion, yielding insights to rabies emergence. In the present study we reconstructed spatiotemporal spread of SCSK in the whole territory of its circulation using a combination of Bayesian methods. The analysis based on 241 glycoprotein gene sequences demonstrated that SCSK is much more divergent phylogenetically than was appreciated previously. According to our analyses the SCSK originated in the territory of Texas ~170 years ago, and spread geographically during the following decades. The wavefront velocity in the northward direction was significantly greater than in the eastward and westward directions. Rivers (except the Mississippi River and Rio Grande River) did not constitute significant barriers for epizootic spread, in contrast to deserts and mountains. The mean dispersal rate of skunk rabies was lower than that of the raccoon and fox rabies. Viral lineages circulate in their areas with limited evidence of geographic spread during decades. However, spatiotemporal reconstruction shows that after a long period of stability the dispersal rate and wavefront velocity of SCSK are increasing. Our results indicate that there is a need to develop control measures for SCSK, and suggest how such measure can be implemented most efficiently. Our approach can be extrapolated to other rabies reservoirs and used as a tool for investigation of epizootic patterns and planning interventions towards disease elimination.


The primary care and other health system use of home care patients: a retrospective cohort analysis.
Robust and integrated primary care and home care are core components of effective chronic disease management in the community. We described the primary care and other health system use by a cohort of home care patients. We conducted a population-based retrospective cohort study of patients who received publicly funded home care in Ontario, Canada, from October 2014 to September 2016. Primary outcomes were primary care physician visits including coordination with home care, home visits and visits after hours or on weekends or holidays within 6 months of a home care assessment. Secondary outcomes included specialist physician visits, emergency department use, home care visits and placement in a long-term care home. Multivariable models examined associations between patient characteristics and subsequent primary care use. There were 226 054 home care patients in our cohort, with a median age of 81 years. Following assessment, home care patients visited primary care physicians at a rate of 0.78 visits per month. Physician-based home care coordination codes were billed for 3.9% of patients. Primary care home visits were received by 13.1% of patients, and 15.1% of patients used primary care after hours or on weekends or holidays. Patients receiving publicly funded home care frequently visited a primary care physician. Physician billings for coordination between primary care and home care were infrequent but were more common in interprofessional primary care practices. Physician home visits were more likely to be received by the oldest and most functionally impaired patients, suggesting that home visits are responsive to the needs of home care patients.


Vectorial coherence holography.
Extension of coherence holography to vectorial regime is investigated. A technique for controlling and synthesizing optical fields with desired elements of coherence-polarization matrix is proposed and experimentally demonstrated. The technique uses two separate coherence holograms, each of which is assigned to one of the orthogonal polarization components of the vectorial fields.


Charge selectivity of proteinuria in diabetic glomerulopathy.
Differential macromolecule clearances were used to elucidate the mechanism of proteinuria in patients with diabetic glomerulopathy. Uncharged dextrans of graded size, combined with albumin and IgG separated into narrow fractions of varying charge by preparative electrofocusing, were used to probe the filtration barrier. Analysis of the fractional clearance profile of dextrans in the 30- to 60-A interval revealed a small fraction of filtrate volume (0.0023-0.0097) permeating large nonrestrictive glomerular pores and correlating strongly with the fractional clearances of albumin (r = .88, P less than .001) or IgG (r = .91, P less than .001). The fractional clearance of the most anionic species of albumin [isoelectric point (pI) 4.0-4.5] significantly exceeded that of less anionic species (pI 4.5-5.5) at all levels of proteinuria. A corresponding increase in fractional clearance of anionic (pI 4.5-5.0) over neutral (pI 7.0-7.5) IgG species was observed in patients with subnephrotic-range proteinuria. We conclude that a loss of barrier size selectivity underlies proteinuria in diabetic glomerulopathy. In addition, either facilitated filtration of polyanions or preferential tubular reabsorption of polycations can be invoked to explain the final composition of urinary protein. Similar loss of size selectivity combined with enhanced fractional clearance of anionic IgG in a group of nondiabetic patients with nephrotic syndrome indicates that the foregoing abnormality of renal protein handling is not unique to diabetic glomerulopathy.


Chronic renal failure from the English-speaking Caribbean: 2007 data.
Development of the renal registry to include patients at different stages of chronic kidney disease (CKD). The 2007 renal registry include cases at different stages of CKD based on the current guidelines according to the National Kidney Foundation (NKF) Kidney Disease Outcome Initiative (K/DOQI) staging. There was an increase in the number of participating countries, with the addition of Antigua and Barbuda, St Lucia and Turks and Caicos. Data were collected using a questionnaire form. Data were stored and analysed in Words Excel for Windows or SPSS 12.0. Data were available for Antigua and Barbuda (n = 43), British Virgin Islands (n = 69), Cayman Islands (n = 45), Trinidad and Tobago (n = 564), Jamaica (n = 920), Turks and Caicos (n = 64), St Lucia (n = 51) and Bahamas (n = 121). The registry identified hypertension, diabetes mellitus and Chronic Glomerulonephritis (CGN) as the commonest causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in these countries. The leading cause of death reported was listed as ischaemic heart disease/heart failure, sepsis and cerebrovascular accident. The majority of patients with CKD and ESRD had hypertension, diabetes mellitus and CGN as the major causes. Collection of data for patients with CKD at different stages was met with some challenges, and resulted in underestimation of the true number of persons with CKD across these Caribbean countries. More emphasis will continue to be placed on improving data collection so the true incidence, prevalence and healthcare burden of CKD is known in the Caribbean. A web based programme is being developed to improve data collection.


TNFR2 increases the sensitivity of ligand-induced activation of the p38 MAPK and NF-κB pathways and signals TRAF2 protein degradation in macrophages.
Tumour necrosis factor (p55 or p60) receptor (TNFR) 1 is the major receptor that activates pro-inflammatory signalling and induces gene expression in response to TNF. Consensus is lacking for the function of (p75 or p80) TNFR2 but experiments in mice have suggested neuro-, cardio- and osteo-protective and anti-inflammatory roles. It has been shown in various cell types to be specifically required for the induction of TNFR-associated factor-2 (TRAF2) degradation and activation of the alternative nuclear factor (NF)-kappaB pathway, and to contribute to the activation of mitogen-activated protein kinases (MAPK) and the classical NF-kappaB pathway. We have investigated the signalling functions of TNFR2 in primary human and murine macrophages. We find that in these cells TNF induces TRAF2 degradation, and this is blocked in TNFR2(-/-) macrophages. TRAF2 has been previously reported to be required for TNF-induced activation of p38 MAPK. However, TRAF2 degradation does not inhibit TNF-induced tolerance of p38 MAPK activation. Neither TNF, nor lipopolysaccharide treatment, induced activation of the alternative NF-kappaB pathway in macrophages. Activation by TNF of the p38 MAPK and NF-kappaB pathways was blocked in TNFR1(-/-) macrophages. In contrast, although TNFR2(-/-) macrophages displayed robust p38 MAPK activation and IkappaBα degradation at high concentrations of TNF, at lower doses the concentration dependence of signalling was weakened by an order of magnitude. Our results suggest that, in addition to inducing TRAF2 protein degradation, TNFR2 also plays a crucial auxiliary role to TNFR1 in sensitising macrophages for the ligand-induced activation of the p38 MAPK and classical NF-kappaB pro-inflammatory signalling pathways.


TRAF6 is an amplified oncogene bridging the RAS and NF-κB pathways in human lung cancer.
Somatic mutations and copy number alterations (as a result of deletion or amplification of large portions of a chromosome) are major drivers of human lung cancers. Detailed analysis of lung cancer-associated chromosomal amplifications could identify novel oncogenes. By performing an integrative cytogenetic and gene expression analysis of non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) cell lines and tumors, we report here the identification of a frequently recurring amplification at chromosome 11 band p13. Within this region, only TNF receptor-associated factor 6 (TRAF6) exhibited concomitant mRNA overexpression and gene amplification in lung cancers. Inhibition of TRAF6 in human lung cancer cell lines suppressed NF-κB activation, anchorage-independent growth, and tumor formation. In these lung cancer cell lines, RAS required TRAF6 for its oncogenic capabilities. Furthermore, TRAF6 overexpression in NIH3T3 cells resulted in NF-κB activation, anchorage-independent growth, and tumor formation. Our findings show that TRAF6 is an oncogene that is important for RAS-mediated oncogenesis and provide a mechanistic explanation for the previously apparent importance of constitutive NF-κB activation in RAS-driven lung cancers.


Dietary Intake Among US Adults, 1999-2012.
Most studies of US dietary trends have evaluated major macronutrients or only a few dietary factors. Understanding trends in summary measures of diet quality for multiple individual foods and nutrients, and the corresponding disparities among population subgroups, is crucial to identify challenges and opportunities to improve dietary intake for all US adults. To characterize trends in overall diet quality and multiple dietary components related to major diseases among US adults, including by age, sex, race/ethnicity, education, and income. Repeated cross-sectional investigation using 24-hour dietary recalls in nationally representative samples including 33,932 noninstitutionalized US adults aged 20 years or older from 7 National Health and Nutrition Examination Survey (NHANES) cycles (1999-2012). The sample size per cycle ranged from 4237 to 5762. Calendar year and population sociodemographic subgroups. Survey-weighted, energy-adjusted mean consumption and proportion meeting targets of the American Heart Association (AHA) 2020 continuous diet scores, AHA score components (primary: total fruits and vegetables, whole grains, fish and shellfish, sugar-sweetened beverages, and sodium; secondary: nuts, seeds, and legumes, processed meat, and saturated fat), and other individual food groups and nutrients. Several overall dietary improvements were identified (P < .01 for trend for each). The AHA primary diet score (maximum of 50 points) improved from 19.0 to 21.2 (an improvement of 11.6%). The AHA secondary diet score (maximum of 80 points) improved from 35.1 to 38.5 (an improvement of 9.7%). Changes were attributable to increased consumption between 1999-2000 and 2011-2012 of whole grains (0.43 servings/d; 95% CI, 0.34-0.53 servings/d) and nuts or seeds (0.25 servings/d; 95% CI, 0.18-0.34 servings/d) (fish and shellfish intake also increased slightly) and to decreased consumption of sugar-sweetened beverages (0.49 servings/d; 95% CI, 0.28-0.70 servings/d). No significant trend was observed for other score components, including total fruits and vegetables, processed meat, saturated fat, or sodium. The estimated percentage of US adults with poor diets (defined as <40% adherence to the primary AHA diet score components) declined from 55.9% to 45.6%, whereas the percentage with intermediate diets (defined as 40% to 79.9% adherence to the primary AHA diet score components) increased from 43.5% to 52.9%. Other dietary trends included increased consumption of whole fruit (0.15 servings/d; 95% CI, 0.05-0.26 servings/d) and decreased consumption of 100% fruit juice (0.11 servings/d; 95% CI, 0.04-0.18 servings/d). Disparities in diet quality were observed by race/ethnicity, education, and income level; for example, the estimated percentage of non-Hispanic white adults with a poor diet significantly declined (53.9% to 42.8%), whereas similar improvements were not observed for non-Hispanic black or Mexican American adults. There was little evidence of reductions in these disparities and some evidence of worsening by income level. In nationally representative US surveys conducted between 1999 and 2012, several improvements in self-reported dietary habits were identified, with additional findings suggesting persistent or worsening disparities based on race/ethnicity, education level, and income level. These findings may inform discussions on emerging successes, areas for greater attention, and corresponding opportunities to improve the diets of individuals living in the United States.


The spontaneous pregnancy prognosis in untreated subfertile couples: the Walcheren primary care study.
The spontaneous pregnancy prognosis of couples in a primary care situation has never been studied. Prognostic models have been developed for referral populations only. We wished to develop a prognostic model to estimate the likelihood of live birth and the impact of prognostic factors among untreated subfertile couples in a primary care situation. With this aim, we conducted a cohort follow-up study of 726 couples in the peninsula of Walcheren, a geographically isolated, but demographically and socio-economically representative area of an industrialized Western society, The Netherlands. Of the Walcheren population, 9.9% exhibit subfertility complaints at least once during their lifetime. There were 201 live birth conceptions during 9915 months of untreated observation. The cumulative rate of conceptions leading to live births was 52.5% when all of the untreated observations were considered, and 72.0% in the subgroup of 342 couples who remained untreated throughout their follow-up. The relevant prognostic factors in this primary care subfertility population were: abnormal post-coital test, tubal defect, ovulation defect, and duration of subfertility. A prediction score based on these factors would be accurate in approximately 76-79% of cases. Live birth prognosis can be estimated with sufficient accuracy to be useful in counselling subfertility patients, and in planning clinical management.


Reframing Non-Communicable Diseases and Injuries for Equity in the Era of Universal Health Coverage: Findings and Recommendations from the Kenya NCDI Poverty Commission.
Kenya has implemented a robust response to non-communicable diseases and injuries (NCDIs); however, key gaps in health services for NCDIs still exist in the attainment of Universal Health Coverage (UHC). The Kenya Non-Communicable Diseases and Injury (NCDI) Poverty Commission was established to estimate the burden of NCDIs, determine the availability and coverage of health services, prioritize an expanded set of NCDI conditions, and propose cost-effective and equity-promoting interventions to avert the health and economic consequences of NCDIs in Kenya. Burden of NCDIs in Kenya was determined using desk review of published literature, estimates from the Global Burden of Disease Study, and secondary analysis of local health surveillance data. Secondary analysis of nationally representative surveys was conducted to estimate current availability and coverage of services by socioeconomic status. The Commission then conducted a structured priority setting process to determine priority NCDI conditions and health sector interventions based on published evidence. There is a large and diverse burden of NCDIs in Kenya, with the majority of disability-adjusted life-years occurring before age of 40. The poorest wealth quintiles experience a substantially higher deaths rate from NCDIs, lower coverage of diagnosis and treatment for NCDIs, and lower availability of NCDI-related health services. The Commission prioritized 14 NCDIs and selected 34 accompanying interventions for recommendation to achieve UHC. These interventions were estimated to cost $11.76 USD per capita annually, which represents 15% of current total health expenditure. This investment could potentially avert 9,322 premature deaths per year by 2030. An expanded set of priority NCDI conditions and health sector interventions are required in Kenya to achieve UHC, particularly for disadvantaged socioeconomic groups. We provided recommendations for integration of services within existing health services platforms and financing mechanisms and coordination of whole-of-government approaches for the prevention and treatment of NCDIs.


Dendritic cell vaccination with MAGE peptide is a novel therapeutic approach for gastrointestinal carcinomas.
The MAGE gene is selectively expressed in cancer tissues such as melanoma or gastrointestinal carcinomas, whereas no expression is observed in normal tissues except testis. There are several reports of successful induction of HLA class I-restricted antitumor CTLs using MAGE peptides, and some clinical trials with these immunogenic peptides were reported as effective for some patients with malignant melanoma. However, there are no similar studies in gastrointestinal carcinomas, which are important neoplasms. Autologous dendritic cells (DCs) were generated ex vivo and were pulsed with MAGE-3 peptide, depending on the patient's HLA haplotype (HLA-A2 or A24). Patients were immunized with DC pulsed with MAGE-3 peptide every 3 weeks at four times. Twelve patients with advanced gastrointestinal carcinoma (six stomach, three esophagus, and three colon) were treated, and no toxic side effects were observed. Peptide-specific CTL responses after vaccination were observed in four of eight patients. Improvement in performance status was recognized in four patients. Tumor markers decreased in seven patients. In addition, minor tumor regressions evidenced by imaging studies were seen in three patients. These results suggested that DC vaccination with MAGE-3 peptide is a safe and promising approach in the treatment of gastrointestinal carcinomas.


Trends in the epidemiology of bacterial sexually transmitted infections in eastern Europe, 1995-2005.
Sexually transmitted infections (STI) are a significant public health problem both worldwide and in Europe. This article reviews trends in the epidemiology of the major bacterial STI in eastern European countries, their key determinants, as well as challenges and opportunities for enhancing STI control in the region. Publications were sought through computerised searches in PubMed from 1995 to 2008 using using free text and relevant medical subject headings with no language restrictions. Conference abstracts and other unpublished manuscripts were excluded. The reported rates of STI in many eastern European countries have either decreased (syphilis and gonorrhoea in the eastern/Russian regions, gonorrhoea throughout eastern Europe) or been relatively stable (syphilis in the southeastern region, chlamydia throughout eastern Europe), in the past decade, but are still significantly higher than in western Europe. There is a significant east-west geopolitical gradient in reported STI rates throughout eastern Europe (STI rates: Russia/eastern region>>southeastern region>central region). Challenges for STI control include: the need to strengthen public health components of control; improvements in surveillance and improvement, as well as quality assurance, in diagnostic strategies. Gains in STI control may be achieved through greater collaboration and harmonisation of practicss at the European level.


The effects of player grip on the dynamic behaviour of a tennis racket.
The aim of this article is to characterise the extent to which the dynamic behaviour of a tennis racket is dependent on its mechanical characteristics and the modulation of the player's grip force. This problem is addressed through steps involving both experiment and modelling. The first step was a free boundary condition modal analysis on five commercial rackets. Operational modal analyses were carried out under "slight", "medium" and "strong" grip force conditions. Modal frequencies and damping factors were then obtained using a high-resolution method. Results indicated that the dynamic behaviour of a racket is not only determined by its mechanical characteristics, but is also highly dependent on the player's grip force. Depending on the grip force intensity, the first two bending modes and the first torsional mode frequencies respectively decreased and increased while damping factors increased. The second step considered the design of a phenomenological hand-gripped racket model. This model is fruitful in that it easily predicts the potential variations in a racket's dynamic behaviour according to the player's grip force. These results provide a new perspective on the player/racket interaction optimisation by revealing how grip force can drive racket dynamic behaviour, and hence underlining the necessity of taking the player into account in the racket design process.


Genetic analysis of the dumpy complex locus in Drosophila melanogaster: complementation, fine structure and function.
An extensive genetic analysis of the dumpy locus is presented. This study includes complementation, fine structure mapping and allelic interaction. A number of complementing recessive lethals of the dp complex have been genetically mapped. Two alleles of the ol(v) type that complement l alleles map to the left portion of the locus. A number of olv alleles that complement both l and lv lethals map within the right portion of the locus.--Fine-structure analysis demonstrated that both olv and o alleles are distributed among various subloci. Evidence for spacer regions between subloci is presented.--An extensive discussion of the data considers whether the locus is unicistronic or multicistronic. The conclusion reached is that the locus is not a single functional cistron. The possibility of a single cistron encoding a multifunctional polypeptide is discussed.--The hypothesis is proposed that the left portion of the map and the l mutations function as regulatory sequences and that the right portion of the map encodes structural sequences.


Timing of indicated late-preterm and early-term birth.
The growing public health awareness of prematurity and its complications has prompted careful evaluation of the timing of deliveries by clinicians and hospitals. Preterm birth is associated with significant morbidity and mortality, and affects more than half a million births in the United States each year. In some situations, however, a late-preterm or early-term birth is the optimal outcome for the mother, child, or both owing to conditions that can result in worse outcomes if pregnancy is allowed to continue. These conditions may be categorized as placental, maternal, or fetal, including conditions such as placenta previa, preeclampsia, and multiple gestations. Some risks associated with early delivery are common to all conditions, including prematurity-related morbidities (eg, respiratory distress syndrome and intraventricular hemorrhage) as well as maternal intrapartum morbidities such as failed induction and cesarean delivery. However, when continuation of the pregnancy is associated with more risks such as hemorrhage, uterine rupture, and stillbirth, preterm delivery maybe indicated. In February 2011, the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Society for Maternal-Fetal Medicine held a workshop titled "Timing of Indicated Late Preterm and Early Term Births." The goal of the workshop was to synthesize the available information regarding conditions that may result in medically indicated late-preterm and early-term births to determine the potential risks and benefits of delivery compared with continued pregnancy, determine the optimal gestational age for delivery of affected pregnancies when possible, and inform future research regarding these issues. Based on available data and expert opinion, optimal timing for delivery for specific conditions was determined by consensus.


Decline in the growth potential of spleen-colonizing bone marrow stem cells of long-lived aging mice.
The growth capacity of femoral bone marrow stem cells from young and old long-lived mice was assessed in the spleen of X-irradiated young and old syngeneic recpients by determining: (a) the number of stem cells colonizing the spleen, (b) the rate of incorporation of 125I-labeled iododeoxyuridine by proliferating colony cells, and (c) the number of cells present in the largest colonies at the end of the growth phase.We found that the growth capacity of stem cells declined with age. We further found that the spleen-seeking and spleen colony growth capacities of old stem cells remained characteristically old even after they were allowed to self-replicate in the bone marrow of young recipients for an extended period of time. On the other hand, the spleen colony growth capacity of young stem cells could be reduced by allowing them to self-replicate in old recipients. These results suggest that the growth capacity of old stem cells is an intrinsic characteristic which cannot be readily altered, but that of young stem cells can be aged in an accelerated manner by allowing them to self-replicate in old recipients. An additional reduction was noted in the frequency of both young and old stem cells colonizing the spleen of old recipients and in the cell density of the largest colonies produced. These results indicate that factors extrinsic to the stem cells are also responsible for the decline with age in their spleen colony growth capacity.Thus, the growth capacity of old stem cells in old recipients could be as low as 10% that of young stem cells in young recipients.


A GPI-linked protein that interacts with Ret to form a candidate neurturin receptor.
Glial-cell-line-derived neurotrophic factor (GDNF) and neurturin (NTN) are two structurally related, potent survival factors for sympathetic, sensory and central nervous system neurons. GDNF mediates its actions through a multicomponent receptor system composed of a ligand-binding glycosyl-phosphatidylinositol (GPI)-linked protein (designated GDNFR-alpha) and the transmembrane protein tyrosine kinase Ret. In contrast, the mechanism by which the NTN signal is transmitted is not well understood. Here we describe the identification and tissue distribution of a GPI-linked protein (designated NTNR-alpha) that is structurally related to GDNFR-alpha. We further demonstrate that NTNR-alpha binds NTN (K[d] approximately 10 pM) but not GDNF with high affinity; that GDNFR-alpha binds to GDNF but not NTN with high affinity; and that cellular responses to NTN require the presence of NTNR-alpha. Finally, we show that NTN, in the presence of NTNR-alpha, induces tyrosine-phosphorylation of Ret, and that NTN, NTNR-alpha and Ret form a physical complex on the cell surface. These findings identify Ret and NTNR-alpha as signalling and ligand-binding components, respectively, of a receptor for NTN and define a novel family of receptors for neurotrophic and differentiation factors composed of a shared transmembrane protein tyrosine kinase and a ligand-specific GPI-linked protein.


Clinician Perspectives of Inpatient Forensic Psychiatric Rehabilitation in a Low Secure Setting: A Qualitative Study.
There is a dearth of research into what low secure forensic psychiatric rehabilitation means in Australia and internationally. The aim of this study was to understand clinician perspectives of forensic psychiatric rehabilitation in a low secure setting in Australia and offer insight into a model of care. A qualitative methodology was chosen with separate semi-structured interviews being conducted with staff members involved in decision-making for forensic psychiatric patients in a rehabilitation unit. Analysis of the interviews identified three domains that the questions related to: 'defining and describing security', 'defining and describing low secure forensic psychiatric rehabilitation' and 'describing the role of staff and services in a low secure forensic psychiatric rehabilitation setting'. Where relevant, themes were abstracted from the questions that related to these domains. This study revealed that clinicians had a varied understanding of definitions for security but a similar understanding of what low secure forensic psychiatric rehabilitation means, what patients are suitable and the general goals of rehabilitation in this setting. Further research is needed on low secure rehabilitation and specific models of care. There is also a need to develop clear definitions for both security and rehabilitation in low secure forensic psychiatric settings.


Rma1, a novel type of RING finger protein conserved from Arabidopsis to human, is a membrane-bound ubiquitin ligase.
Rma1 is a protein with a RING finger motif and a C-terminal membrane-anchoring domain and is well conserved among higher eukaryotes. We show that fusion proteins between maltose binding protein (MBP) and human or Arabidopsis Rma1 are polyubiquitinated, when incubated with the rabbit reticulocyte or the wheat germ lysate, respectively. The polyubiquitination of MBP-Rma1 has been reconstituted by incubation with purified ubiquitin, the ubiquitin-activating enzyme E1, and one of the two ubiquitin-conjugating E2 enzymes (Ubc4 or UbcH5a). Other E2 enzymes tested, E2-20k, E2-25k, Ubc3 and Ubc8, are not able to confer this modification. Mutational analysis shows that the RING finger motif of Rma1 is necessary for the auto-ubiquitination of MBP-Rma1. Thus, Rma1 represents a novel, membrane-bound type of ubiquitin ligase E3, which probably functions with the Ubc4/5 subfamily of E2. The MBP moiety but not Rma1 itself is ubiquitinated in the auto-ubiquitination reaction of MBP-Rma1. Free MBP in solution is not a substrate of Rma1. These observations indicate that bringing the substrate into its physical vicinity is very important for the action of ubiquitin ligase.


On the coexistence of competing microbial species in a chemostat under cycling.
It is known that two microbial species competing for a single rate-limiting nutrient cannot grow together in a chemostat under steady-state operation, but eventually the species with the lower specific growth rate at the particular operating conditions will become extinct. Coexistence of the two populations has been shown obtainable in chemostats under periodic operation. This is possible in cases where the specific growth rate functions of the two species are such that for certain values of the nutrient concentration the first species grows faster than the second, and for other values of the nutrient concentration the second species is the one growing faster. In a previous article it was demonstrated that, even in cases where the specific growth rate functions of the two species are such that one of the species grows faster than the other for all values of the nutrient concentration, extinction of either species is possible provided that time delay in the response of the species to changes in their fermentation environment is accounted for, and that the faster growing species is also faster in its response. Here, we show that coexistence of the two species is also possible in a significant range of the operating parameters. We develop a numerical algorithm with which we trace the boundary of the coexistence region in the entire operating parameter space and construct the operating diagram of the system.


Clinical challenges and controversies in the management of HIV/ HCV-coinfected individuals.
The natural history of HIV infection has been dramatically changed by the highly active antiretroviral therapies, reducing complications, morbidity and mortality of the disease. Approximately 25% of persons infected with HIV are co-infected with hepatitis C, and some high risk populations have a prevalence of HCV of more than 75%. Liver disease has become one of the principal causes of morbidity and mortality in this population. Co-infection increases viremia of hepatitis C, with increase in fibrosis progression, cirrhosis and death related to hepatitis C. The permanent state of chronic immune activation related to the persistent hepatitis C virus favors transcription of HIV in infected cells and causes a more rapid destruction of T4 and absolute lymphocytes. In addition, the immunologic response after the start of highly active antiretroviral therapy for HIV is less than in mono-infected patients. The role of liver biopsy in the management of co-infected patients is controversial. Many of these patients, even with normal transaminases, show fibrosis in liver biopsy. Predictive factors for advanced fibrosis include male sex, alcohol consumption in excess of 50 grams per day, age over 35, and HIV infection of more than 15 years with CD4 lymphocytes less than 400/ mm3. The treatment of hepatitis C is limited and sustained viral response is less than 30% for genotypes 1 and 4. This response is even less in the more advanced stages of HIV and hepatitis C. The determination of when to start treatment and the increased toxicity when combining pegylated interferon plus ribavirin and antiretroviral medications makes the management of these patients more difficult. The development of more potent, safe and tolerated medications is required. Management strategies for patients unresponsive to conventional therapy are geared towards improving liver histology and delaying progression to cirrhosis, hepatocellular cancer and liver transplantation.


Comparative effect of manuka honey on anaerobic parasitic protozoans with standard drug therapy under in vitro conditions: A preliminary study.
From the past five decades, metronidazole and tinidazole have been used for treating nonresistant and resistant giardiasis and trichomoniasis. However, due to the occurrence of drug resistance to standard therapy idealizes us to explore some additional therapies which is cost-effective, easy accessibility, and natural which has least side effects. Manuka honey obtained from Leptospermum scoparium is well known for its antibacterial and wound healing properties and is thought to be a better option as an additional therapy. The present study was conducted to find out the effect of manuka honey on anaerobic protozoans that includes Giardia and Trichomonas under in vitro conditions in comparison to metronidazole and tinidazole. Axenic culture of Giardia lamblia strain Portland 1 and Trichomonas vaginalis strain 413 was used for drug sensitivity assay to tinidazole, metronidazole, and manuka honey with the highest concentration of 17.1 μg/ml, 24.7 μg/ml, and 50%v/v by using (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, a tetrazole). For this, head-to-head comparison has been done and IC 50 of the standard drug as well as manuka honey was calculated. The result showed that percentage inhibition on the growth of both the parasites is dependent on concentration as well as exposure time of the drug. The calculated IC 50 was found to be 5.6%v/v and 1.5%v/v for manuka honey with respect to G. lamblia and T. vaginalis. The present study suggests that manuka honey can be used as an additional therapy for the patient with giardiasis or trichomoniasis. However, in vivo study in the near future will elucidate more about the effectiveness of honey in treating parasitic infections.


Environmental and Intrinsic Correlates of Stress in Free-Ranging Wolves.
When confronted with a stressor, animals react with several physiological and behavioral responses. Although sustained or repeated stress can result in severe deleterious physiological effects, the causes of stress in free-ranging animals are yet poorly documented. In our study, we aimed at identifying the main factors affecting stress levels in free-ranging wolves (Canis lupus). We used fecal cortisol metabolites (FCM) as an index of stress, after validating the method for its application in wolves. We analyzed a total of 450 fecal samples from eleven wolf packs belonging to three protected populations, in Italy (Abruzzo), France (Mercantour), and the United States (Yellowstone). We collected samples during two consecutive winters in each study area. We found no relationship between FCM concentrations and age, sex or social status of individuals. At the group level, our results suggest that breeding pair permanency and the loss of pack members through processes different from dispersal may importantly impact stress levels in wolves. We measured higher FCM levels in comparatively small packs living in sympatry with a population of free-ranging dogs. Lastly, our results indicate that FCM concentrations are associated with endoparasitic infections of individuals. In social mammals sharing strong bonds among group members, the death of one or several members of the group most likely induces important stress in the remainder of the social unit. The potential impact of social and territorial stability on stress levels should be further investigated in free-ranging populations, especially in highly social and in territorial species. As persistent or repeated stressors may facilitate or induce pathologies and physiological alterations that can affect survival and fitness, we advocate considering the potential impact of anthropogenic causes of stress in management and conservation programs regarding wolves and other wildlife.


Sensory reweighting dynamics in human postural control.
Healthy humans control balance during stance by using an active feedback mechanism that generates corrective torque based on a combination of movement and orientation cues from visual, vestibular, and proprioceptive systems. Previous studies found that the contribution of each of these sensory systems changes depending on perturbations applied during stance and on environmental conditions. The process of adjusting the sensory contributions to balance control is referred to as sensory reweighting. To investigate the dynamics of reweighting for the sensory modalities of vision and proprioception, 14 healthy young subjects were exposed to six different combinations of continuous visual scene and platform tilt stimuli while sway responses were recorded. Stimuli consisted of two components: 1) a pseudorandom component whose amplitude periodically switched between low and high amplitudes and 2) a low-amplitude sinusoidal component whose amplitude remained constant throughout a trial. These two stimuli were mathematically independent of one another and, thus, permitted separate analyses of sway responses to the two components. For all six stimulus combinations, the sway responses to the constant-amplitude sine were influenced by the changing amplitude of the pseudorandom component in a manner consistent with sensory reweighting. Results show clear evidence of intra- and intermodality reweighting. Reweighting dynamics were asymmetric, with slower reweighting dynamics following a high-to-low transition in the pseudorandom stimulus amplitude compared with low-to-high amplitude shifts, and were also slower for inter- compared with intramodality reweighting.


Modeling the impact of prevention policies on future diabetes prevalence in the United States: 2010-2030.
Although diabetes is one of the most costly and rapidly increasing serious chronic diseases worldwide, the optimal mix of strategies to reduce diabetes prevalence has not been determined. Using a dynamic model that incorporates national data on diabetes prevalence and incidence, migration, mortality rates, and intervention effectiveness, we project the effect of five hypothetical prevention policies on future US diabetes rates through 2030: 1) no diabetes prevention strategy; 2) a "high-risk" strategy, wherein adults with both impaired fasting glucose (IFG) (fasting plasma glucose of 100-124 mg/dl) and impaired glucose tolerance (IGT) (2-hour post-load glucose of 141-199 mg/dl) receive structured lifestyle intervention; 3) a "moderate-risk" strategy, wherein only adults with IFG are offered structured lifestyle intervention; 4) a "population-wide" strategy, in which the entire population is exposed to broad risk reduction policies; and 5) a "combined" strategy, involving both the moderate-risk and population-wide strategies. We assumed that the moderate- and high-risk strategies reduce the annual diabetes incidence rate in the targeted subpopulations by 12.5% through 2030 and that the population-wide approach would reduce the projected annual diabetes incidence rate by 2% in the entire US population. We project that by the year 2030, the combined strategy would prevent 4.6 million incident cases and 3.6 million prevalent cases, attenuating the increase in diabetes prevalence by 14%. The moderate-risk approach is projected to prevent 4.0 million incident cases, 3.1 million prevalent cases, attenuating the increase in prevalence by 12%. The high-risk and population approaches attenuate the projected prevalence increases by 5% and 3%, respectively. Even if the most effective strategy is implemented (the combined strategy), our projections indicate that the diabetes prevalence rate would increase by about 65% over the 23 years (i.e., from 12.9% in 2010 to 21.3% in 2030). While implementation of appropriate diabetes prevention strategies may slow the rate of increase of the prevalence of diabetes among US adults through 2030, the US diabetes prevalence rate is likely to increase dramatically over the next 20 years. Demand for health care services for people with diabetes complications and diabetes-related disability will continue to grow, and these services will need to be strengthened along with primary diabetes prevention efforts.


Winter is coming: nightmares and sleep problems during seasonal affective disorder.
Sleep problems, especially nightmares and insomnia, often accompany depression. This study investigated how nightmares, symptoms of insomnia, chronotype and sleep duration associate with seasonal affective disorder, a special form of depression. Additionally, it was noted how latitude, a proxy for photoperiod, and characteristics of the place of residence affect the prevalence of seasonal affective disorder and sleep problems. To study these questions, data from FINRISK 2012 study were used. FINRISK 2012 consists of a random population sample of Finnish adults aged 25-74 years (n = 4905) collected during winter from Finnish urban and rural areas spanning the latitudes of 60°N to 66°N. The Seasonal Pattern Assessment Questionnaire was used to assess symptoms of seasonal affective disorder. Participants with symptoms of seasonal affective disorder had significantly increased odds of experiencing frequent nightmares and symptoms of insomnia, and they were more often evening chronotypes. Associations between latitude, population size and urbanicity with seasonal affective disorder symptoms and sleep disturbances were generally not significant, although participants living in areas bordering urban centres had less sleep problems than participants from other regions. These data show that the prevalence of seasonal affective disorder was not affected by latitude.


Analysis of the gas phase of cigarette smoke by gas chromatography coupled with UV-diode array detection.
A gas chromatography method, coupled with diode array photometric spectral detection in the ultraviolet region (167-330 nm), was developed for the analysis of the gas phase of cigarette smoke. The method enabled us to identify more than 20 volatiles present in the vapor phase of cigarette smoke. In that way, all major volatile organic compounds (including aldehydes, conjugated dienes, ketones, sulfides, furans, and single-ring aromatics), as well as nitric oxide (NO) and hydrogen sulfide (H(2)S), can be analyzed in a straightforward manner through a single chromatographic run of <50-min duration. The method can easily be applied by the introduction of a small volume of the gas-phase stream into the GC injection loop directly through the smoking apparatus exhaust circuit, thus providing an excellent alternative to available methods, which usually require extraction or concentration steps prior to any chromatographic analysis. Furthermore, all problems concerning aging of the gas phase are eliminated. Twelve compounds (including NO) were chosen for quantification through the use of appropriate calibration standards. Comparison of the vapor phase yields of these compounds for the reference cigarette Kentucky 1R4F with already reported data indicates that this method is very reliable as far as accuracy and reproducibility of the results are concerned. Finally, the proposed methodology was used to compare the concentration of these cigarette smoke gas-phase constituents among individual puffs.


Effect of Abutment Geometry and Luting Agents on the Vertical Marginal Discrepancy of Cast Copings on Implant Abutments: An In Vitro Study.
Vertical marginal discrepancy (VMD) influences the success of implant-supported restorations. However, there is little literature that has investigated the influence of geometry and cementing agent on changes in VMD of metal copings on implant abutments. The objective was to evaluate the effect of the geometry of the abutment and cementing agents on VMD. Cast copings were cemented on implant abutments customized cylindrical (4, 5.5, and 7 mm) and on hexagonal implant abutments (4 mm) cemented or uncemented molded copings were placed (n = 4, totally 64 samples) with different luting agents. The VMD of the copings were measured in the coping-abutment interface at three reference points using a stereomicroscope. The independent Student's t test was used for comparison between the two different abutment walls. The post hoc statistical analysis was performed by the Tukey test. There was a significant VMD increase between noncemented and cemented cast copings using different luting agents. Abutment geometry and luting agents significantly influenced the VMD (p ≤ 0.05). Cylindrical abutment at 7 mm in height cemented with different luting agent tested showed significantly higher VMD values than cylindrical abutments of 4 mm (p=0.019). Hexagonal abutments with a 4 mm height showed significantly higher VMD values than cylindrical 4 mm abutments using zinc oxide noneugenol and glass ionomer cements (p=0.032). Abutment geometry and luting agents influence the VMD of cast copings cemented on implant abutment. The higher the cylindrical abutment, the greater the VMD, and hexagonal wall abutments promote greater marginal gap.


Reduced plantarflexor specific torque in the elderly is associated with a lower activation capacity.
Previous studies have reported a decrease in muscle torque per cross-sectional area in old age. This investigation aimed at determining the influence of agonists muscle activation and antagonists co-activation on the specific torque of the plantarflexors (PF) in recreationally active elderly males (EM) and, for comparison, in young men (YM). Twenty-one EM, aged 70-82 years, and 14 YM, aged 19-35 years, performed isometric maximum voluntary contractions (MVC). Activation was assessed by comparing the amplitude of interpolated supramaximal twitch doublets at MVC, with post-tetanic doublet peak torque. Co-activation of the tibialis anterior (TA) was evaluated as the ratio of TA-integrated EMG (IEMG) activity during PF MVC compared to TA IEMG during maximal voluntary dorsiflexion. Triceps surae muscle volume (VOL) was assessed using magnetic resonance imaging (MRI), and PF peak torque was normalised to VOL (PT/VOL) since the later approximates physiological cross-sectional area (CSA) more closely than anatomical CSA. Also, physical activity level, assessed by accelerometry, was significantly lower (21%) in the elderly males. In comparison to the YM group, a greater difference in PT (39%) than VOL (19%) was found in the EM group. PT/VOL and activation capacity were respectively lower by 25% and 21% in EM compared to YM, whereas co-activation was not significantly different. In EM PT/VOL correlated with activation (R(2)=0.31, P<0.01). In conclusion, a reduction in activation capacity may contribute significantly to the decline in specific torque in the plantar flexors of elderly males. The hypothesis is put forward that reduced physical activity is partialy responsible for the reduced activation capacity in the elderly.


HDX-MS reveals orthosteric and allosteric changes in apolipoprotein-D structural dynamics upon binding of progesterone.
Apolipoprotein-D is a glycosylated tetrameric lipocalin that binds and transports small hydrophobic molecules such as progesterone and arachidonic acid. Like other lipocalins, apolipoprotein-D adopts an eight-stranded β-barrel fold stabilized by two intramolecular disulphide bonds, with an adjacent α-helix. Crystallography studies of recombinant apolipoprotein-D demonstrated no major conformational changes upon progesterone binding. Amide hydrogen-deuterium exchange mass spectrometry (HDX-MS) reports structural changes of proteins in solution by monitoring exchange of amide hydrogens in the protein backbone with deuterium. HDX-MS detects changes in conformation and structural dynamics in response to protein function such as ligand binding that may go undetected in X-ray crystallography, making HDX-MS an invaluable orthogonal technique. Here, we report an HDX-MS protocol for apolipoprotein-D that solved challenges of high protein rigidity and low pepsin cleavage using rigorous quenching conditions and longer deuteration times, yielding 85% sequence coverage and 50% deuterium exchange. The relative fractional deuterium exchange of ligand-free apolipoprotein-D revealed apolipoprotein-D to be a highly structured protein. Progesterone binding was detected by significant reduction in deuterium exchange in eight peptides. Stabilization of apolipoprotein-D dynamics can be interpreted as a combined orthosteric effect in the ligand binding pocket and allosteric effect at the N-terminus and C-terminus. Together, our experiments provide insight into apolipoprotein-D structural dynamics and map the effects of progesterone binding that are relayed to distal parts of the protein. The observed stabilization of apolipoprotein-D dynamics upon progesterone binding demonstrates a common behaviour in the lipocalin family and may have implications for interactions of apolipoprotein-D with receptors or lipoprotein particles. Statement: We reveal for the first time how apolipoprotein-D, which is protective in Alzheimer's disease, becomes more ordered when bound to a molecule of steroid hormone. These results significantly extend the understanding of apolipoprotein-D structure from X-ray crystallography studies by incorporating information on how protein motion changes over time. To achieve these results an improved protocol was developed, suitable for proteins similar to apolipoprotein-D, to elucidate how proteins change flexibility when binding to small molecules.


Dapsone-induced hemolytic anemia: effect of dapsone hydroxylamine on sulfhydryl status, membrane skeletal proteins and morphology of human and rat erythrocytes.
Dapsone hydroxylamine is a direct-acting hemolytic agent responsible for dapsone-induced hemolytic anemia in the rat. In the present study, we compared the responsiveness of rat and human red cells to dapsone hydroxylamine-induced cellular changes. Dapsone hydroxylamine induced a rapid and concentration-dependent loss of erythrocytic reduced glutathione content with a concomitant increase in protein-glutathione mixed disulfide formation in both human and rat red cell suspensions. However, the rate of mixed disulfide formation in human cells was considerably slower than that in rat cells and was preceded by a transient increase in oxidized glutathione (glutathione disulfide) formation. Sodium dodecylsulfate-polyacrylamide gel electrophoresis and immunoblotting analysis of membrane ghosts from human red cells revealed changes in skeletal proteins that in general were similar to those observed with rat cells, including a loss of protein band 2.1 and the appearance of membrane-bound hemoglobin. Notable differences were the resistance to loss of band 4.2 and a considerably higher amount of protein aggregation in human ghosts. Although the morphology of human red cells was altered, the incidence and degree of change were considerably less than those of rat red cells. Furthermore, the concentration of dapsone hydroxylamine required to induce damage in human red cells (175-750 microM) was significantly higher than that required for rat red cells (50-175 microM), suggesting that human cells are probably less sensitive than rat cells to dapsone hydroxylamine-induced oxidative damage.


LOFAR Lightning Imaging: Mapping Lightning With Nanosecond Precision.
Lightning mapping technology has proven instrumental in understanding lightning. In this work we present a pipeline that can use lightning observed by the LOw-Frequency ARray (LOFAR) radio telescope to construct a 3-D map of the flash. We show that LOFAR has unparalleled precision, on the order of meters, even for lightning flashes that are over 20 km outside the area enclosed by LOFAR antennas (∼3,200 km2), and can potentially locate over 10,000 sources per lightning flash. We also show that LOFAR is the first lightning mapping system that is sensitive to the spatial structure of the electrical current during individual lightning leader steps.


New devices for TAVI: technologies and initial clinical experiences.
Treatment of aortic stenosis in high-risk surgical patients has been modified in the past 10 years owing to the introduction of transcatheter aortic valve implantation (TAVI). Several issues affecting outcomes with implantation of the first-generation TAVI devices remain unresolved, including haemorrhagic and vascular complications, neurological events, rhythm disturbances, and paravalvular leakage. Further technological improvements are, therefore, required before the indications for TAVI can be extended to young and low-risk patients with aortic stenosis. Many new-generation TAVI devices are currently in the early stages of clinical evaluation. Modifications in the new devices include the ability to reposition the valve before final deployment, features to reduce paravalvular leakage, and the introduction of low-profile delivery systems. The aim of this Review is to provide an overview of the new-generation transcatheter valvular technologies, including initial clinical reports.


Blue Light Protects Against Temporal Frequency Sensitive Refractive Changes.
Time spent outdoors is protective against myopia. The outdoors allows exposure to short-wavelength (blue light) rich sunlight, while indoor illuminants can be deficient at short-wavelengths. In the current experiment, we investigate the role of blue light, and temporal sensitivity, in the emmetropization response. Five-day-old chicks were exposed to sinusoidal luminance modulation of white light (with blue; N = 82) or yellow light (without blue; N = 83) at 80% contrast, at one of six temporal frequencies: 0, 0.2, 1, 2, 5, 10 Hz daily for 3 days. Mean illumination was 680 lux. Changes in ocular components and corneal curvature were measured. Refraction, eye length, and choroidal changes were dependent on the presence of blue light (P < 0.03, all) and on temporal frequency (P < 0.03, all). In the presence of blue light, refraction did not change across frequencies (mean change -0.24 [diopters] D), while in the absence of blue light, we observed a hyperopic shift (>1 D) at high frequencies, and a myopic shift (>-0.6 D) at low frequencies. With blue light there was little difference in eye growth across frequencies (77 μm), while in the absence of blue light, eyes grew more at low temporal frequencies and less at high temporal frequencies (10 vs. 0.2 Hz: 145 μm; P < 0.003). Overall, neonatal astigmatism was reduced with blue light. Illuminants rich in blue light can protect against myopic eye growth when the eye is exposed to slow changes in luminance contrast as might occur with near work.


A robust H.264/AVC video watermarking scheme with drift compensation.
A robust H.264/AVC video watermarking scheme for copyright protection with self-adaptive drift compensation is proposed. In our scheme, motion vector residuals of macroblocks with the smallest partition size are selected to hide copyright information in order to hold visual impact and distortion drift to a minimum. Drift compensation is also implemented to reduce the influence of watermark to the most extent. Besides, discrete cosine transform (DCT) with energy compact property is applied to the motion vector residual group, which can ensure robustness against intentional attacks. According to the experimental results, this scheme gains excellent imperceptibility and low bit-rate increase. Malicious attacks with different quantization parameters (QPs) or motion estimation algorithms can be resisted efficiently, with 80% accuracy on average after lossy compression.


A formal perturbation equation between genotype and phenotype determines the Evolutionary Action of protein-coding variations on fitness.
The relationship between genotype mutations and phenotype variations determines health in the short term and evolution over the long term, and it hinges on the action of mutations on fitness. A fundamental difficulty in determining this action, however, is that it depends on the unique context of each mutation, which is complex and often cryptic. As a result, the effect of most genome variations on molecular function and overall fitness remains unknown and stands apart from population genetics theories linking fitness effect to polymorphism frequency. Here, we hypothesize that evolution is a continuous and differentiable physical process coupling genotype to phenotype. This leads to a formal equation for the action of coding mutations on fitness that can be interpreted as a product of the evolutionary importance of the mutated site with the difference in amino acid similarity. Approximations for these terms are readily computable from phylogenetic sequence analysis, and we show mutational, clinical, and population genetic evidence that this action equation predicts the effect of point mutations in vivo and in vitro in diverse proteins, correlates disease-causing gene mutations with morbidity, and determines the frequency of human coding polymorphisms, respectively. Thus, elementary calculus and phylogenetics can be integrated into a perturbation analysis of the evolutionary relationship between genotype and phenotype that quantitatively links point mutations to function and fitness and that opens a new analytic framework for equations of biology. In practice, this work explicitly bridges molecular evolution with population genetics with applications from protein redesign to the clinical assessment of human genetic variations.


The metabolism of thymol by a Pseudomonas.
1. Pseudomonas putida when grown with thymol contained a meta-fission dioxygenase, which required ferrous ions and readily cleaved the benzene nucleus of catechols between adjacent carbon atoms bearing hydroxyl and isopropyl groups. 2. 3-Hydroxythymo-1,4-quinone was excreted towards the end of exponential growth and later was slowly metabolized. This compound was oxidized by partially purified extracts only when NADH was supplied; the substrate for the dioxygenase appeared to be 3-hydroxythymo-1,4-quinol, which was readily and non-enzymically oxidized to the quinone. 3. 2-Oxobutyrate (0.9 mole) was formed from 1 mole of 3-hydroxythymo-1,4-quinone with the consumption of 1 mole of oxygen; acetate, isobutyrate and 2-hydroxybutyrate (which arose from the enzymic reduction of 2-oxobutyrate) were also formed. 4. These products, which were produced only when the catechol substrate contained a third hydroxyl group, appeared to result from the enzymic hydrolysis of the ring-fission product.


Efficacy of a continuous, multiagent chemotherapeutic protocol versus a short-term single-agent protocol in dogs with lymphoma.
To compare response rates and remission and survival times in dogs with lymphoma treated with a continuous, multiagent, doxorubicin-based chemotherapeutic protocol or with a short-term single-agent protocol incorporating doxorubicin. Nonrandomized controlled clinical trial. 114 dogs with lymphoma. Dogs were treated with a chemotherapeutic protocol consisting of L-asparaginase, vincristine, cyclophosphamide, doxorubicin, methotrexate, and prednisolone (n=87) or doxorubicin alone (27). 63 of 86 (73%) dogs treated with the multiagent protocol (data on response was unavailable for 1 dog) and 14 of 27 (52%) dogs treated with the single-agent protocol had a complete remission. Dogs with lymphoma classified as substage<or=and dogs with a high BUN concentration at the time of initial diagnosis were significantly less likely to have a complete remission. No significant difference in remission or survival time could be demonstrated between treatment groups. Incidence of hematologic and gastrointestinal tract toxicoses did not differ between treatment groups, with the exception that vomiting was more common among dogs treated with the multiagent protocol. In this population of dogs, we were not able to identify any significant difference in remission or survival times between dogs with lymphoma treated with a continuous, multiagent chemotherapeutic protocol and dogs treated with a short-term single-agent protocol involving doxorubicin.


Homoeologs: What Are They and How Do We Infer Them?
The evolutionary history of nearly all flowering plants includes a polyploidization event. Homologous genes resulting from allopolyploidy are commonly referred to as 'homoeologs', although this term has not always been used precisely or consistently in the literature. With several allopolyploid genome sequencing projects under way, there is a pressing need for computational methods for homoeology inference. Here we review the definition of homoeology in historical and modern contexts and propose a precise and testable definition highlighting the connection between homoeologs and orthologs. In the second part, we survey experimental and computational methods of homoeolog inference, considering the strengths and limitations of each approach. Establishing a precise and evolutionarily meaningful definition of homoeology is essential for understanding the evolutionary consequences of polyploidization.


Impurity cyclotron resonance of anomalous Dirac electrons in graphene.
We have investigated a new feature of impurity cyclotron resonances common to various localized potentials of graphene. A localized potential can interact with a magnetic field in an unexpected way in graphene. It can lead to formation of anomalous boundstates that have a sharp peak with a width R in the probability density inside the potential and a broad peak of size magnetic length ℓ outside the potential. We investigate optical matrix elements of anomalous states and find that they are unusually small and depend sensitively on the magnetic field. The effect of many-body interactions on their optical conductivity is investigated using a self-consistent time-dependent Hartree-Fock approach. For a completely filled Landau level we find that an excited electron-hole pair, originating from the optical transition between two anomalous impurity states, is nearly uncorrelated with other electron-hole pairs, although it displays substantial exchange self-energy effects. This absence of correlation is a consequence of a small vertex correction in comparison to the difference between renormalized transition energies computed within the one electron-hole pair approximation. However, an excited electron-hole pair originating from the optical transition between a normal and an anomalous impurity state can be substantially correlated with other electron-hole states with a significant optical strength.


Enhanced air stability of polymer solar cells with a nanofibril-based photoactive layer.
In spite of the rapid increase in the power conversion efficiency (PCE) of polymer solar cells (PSCs), the poor stability of the photoactive layer in air under sunlight is a critical problem blocking commercialization of PSCs. This study investigates the photo-oxidation behavior of a bulk-heterojunction (BHJ) photoactive film made of single-crystalline poly(3-hexlythiophene) (P3HT) nanofibrils and fullerene derivatives [phenyl-C61-butyric methyl ester (PCBM), indene-C 60 bisadduct (ICBA)]. Because the single-crystalline P3HT nanofibrils had tightly packed π-π stacking, the permeation of oxygen and water into the nanofibrils was significantly reduced. Chemical changes in P3HT were not apparent in the nanofibrils, and hence the air stability of the nanofibril-based BHJ film was considerably enhanced as compared with conventional BHJ films. The chemical changes were monitored by Fourier-transform infrared (FT-IR) spectroscopy, Raman spectroscopy, and UV-vis absorbance. Inverted PSCs made of the nanofibril-based BHJ layer also showed significantly enhanced air stability under sunlight. The nanofibril-based solar cell maintained more than 80% of its initial PCE after 30 days of continuous exposure to sunlight (AM 1.5G, 100 mW/cm(2)), whereas the PCE of the conventional BHJ solar cell decreased to 20% of its initial PCE under the same experimental conditions.


Investigation of Pathophysiological Aspects of Aortic Growth, Remodeling, and Failure Using a Discrete-Fiber Microstructural Model.
Aortic aneurysms are inherently unpredictable. One can never be sure whether any given aneurysm may rupture or dissect. Clinically, the criteria for surgical intervention are based on size and growth rate, but it remains difficult to identify a high-risk aneurysm, which may require intervention before the cutoff criteria, versus an aneurysm than can be treated safely by more conservative measures. In this work, we created a computational microstructural model of a medial lamellar unit (MLU) incorporating (1) growth and remodeling laws applied directly to discrete, individual fibers, (2) separate but interacting fiber networks for collagen, elastin, and smooth muscle, (3) active and passive smooth-muscle cell mechanics, and (4) failure mechanics for all three fiber types. The MLU model was then used to study different pathologies and microstructural anomalies that may play a role in vascular growth and failure. Our model recapitulated many aspects of arterial remodeling under hypertension with no underlying genetic syndrome including remodeling dynamics, tissue mechanics, and failure. Syndromic effects (smooth muscle cell (SMC) dysfunction or elastin fragmentation) drastically changed the simulated remodeling process, tissue behavior, and tissue strength. Different underlying pathologies were able to produce similarly dilatated vessels with different failure properties, providing a partial explanation for the imperfect nature of aneurysm size as a predictor of outcome.


Dopaminergic Mechanisms Underlying Normal Variation in Trait Anxiety.
Trait anxiety has been associated with altered activity within corticolimbic pathways connecting the amygdala and rostral anterior cingulate cortex (rACC), which receive rich dopaminergic input. Though the popular culture uses the term "chemical imbalance" to describe the pathophysiology of psychiatric conditions such as anxiety disorders, we know little about how individual differences in human dopamine neurochemistry are related to variation in anxiety and activity within corticolimbic circuits. We addressed this issue by examining interindividual variability in dopamine release at rest using [11C]raclopride positron emission tomography (PET), functional connectivity between amygdala and rACC using resting-state functional magnetic resonance imaging (fMRI), and trait anxiety measures in healthy adult male and female humans. To measure endogenous dopamine release, we collected two [11C]raclopride PET scans per participant. We contrasted baseline [11C]raclopride D2/3 receptor binding and D2/3 receptor binding following oral methylphenidate administration. Methylphenidate blocks the dopamine transporter, which increases extracellular dopamine and leads to reduced [11C]raclopride D2/3 receptor binding via competitive displacement. We found that individuals with higher dopamine release in the amygdala and rACC self-reported lower trait anxiety. Lower trait anxiety was also associated with reduced rACC-amygdala functional connectivity at baseline. Further, functional connectivity showed a modest negative relationship with dopamine release such that reduced rACC-amygdala functional connectivity was accompanied by higher levels of dopamine release in these regions. Together, these findings contribute to hypodopaminergic models of anxiety and support the utility of combining fMRI and PET measures of neurochemical function to advance our understanding of basic affective processes in humans.SIGNIFICANCE STATEMENT It is common wisdom that individuals vary in their baseline levels of anxiety. We all have a friend or colleague we know to be more "tightly wound" than others, or, perhaps, we are the ones marveling at others' ability to "just go with the flow." Although such observations about individual differences within nonclinical populations are commonplace, the neural mechanisms underlying normal variation in trait anxiety have not been established. Using multimodal brain imaging in humans, this study takes initial steps in linking intrinsic measures of neuromodulator release and functional connectivity within regions implicated in anxiety disorders. Our findings suggest that in healthy adults, higher levels of trait anxiety may arise, at least in part, from reduced dopamine neurotransmission.


The abundance and seasonal distribution of Culex mosquitoes in Iowa during 1995-97.
The abundance and seasonal distribution of Culex mosquitoes were monitored by measuring oviposition activity during the summers of 1995, 1996, and 1997. Five species of culicine mosquitoes laid egg rafts in ovitraps. Egg rafts of 4 Culex species-Cx. restuans (54.98%), Cx. pipiens (25.41%), Cx. salinarius (12.18%), and Cx. tarsalis (0.14%)-constituted more than 92% of the total egg rafts collected. Culiseta inornata (0.1%) was the only other species to lay viable egg rafts in the ovitraps. A small percentage (7.19%) of egg rafts did not hatch; thus identification was not possible. Compared with New Jersey light trap data in a nearby area, the abundance of Cx. tarsalis and Cs. inornata was markedly underestimated with ovitraps. These data may also reflect differences in the specific location of the 2 trap sites rather than attractiveness of ovitraps for Cx. tarsalis and Cs. inornata. In general, Cx. restuans oviposition activity began in late May, and it was the dominant Culex species through June. After July 1, the number of egg rafts laid by Cx. restuans decreased continually until the end of the summer. Culex pipiens and Cx. salinarius oviposition began in early June and increased gradually during the summer. Over the course of a summer, there were about twice as many Cx. pipiens as there were Cx. salinarius. A crossover in the number of Cx. pipiens and Cx. restuans egg rafts occurred in late July or early August, depending on the year. By late August each year, Cx. pipiens was the most abundant species. At this time, Cx. restuans and Cx. salinarius populations were similar, but each was about half of the Cx. pipiens population. Differences in the abundance of all 3 species could not be explained by changes in ambient temperature (both minimum and maximum) or relative humidity, either within or among years.


Expression of beta human chorionic gonadotrophin by non-trophoblastic non-endocrine 'normal' and malignant epithelial cells.
Expression of hCG and its free subunits by non-trophoblastic tumours is well recognised. Previously we reported hCG secretion by normal and malignant bladder epithelial cells in vitro. Here we examined culture medium from 83 different cell lines derived mainly from common epithelial tumours. Thirty-two of the cell lines were found to secrete hCG-like material into their culture media. Partial immunochemical characterisation showed that of these only choriocarcinoma and fetal tissue cell lines produced intact hCG and alpha subunit. The remaining 28 hCG-expressing epithelial cell lines, which are of mucosal origin, only secreted free beta subunit. Expression of free beta hCG by non-trophoblastic nonendocrine cells would appear to be especially characteristic of mucosal epithelia from the genitourinary and oral/respiratory tracts. Furthermore, this phenomenon may be characteristic of epithelium with transitional and/or squamous cell-like properties.


Analgesic Use and Risk for Acute Coronary Events in Patients With Osteoarthritis: A Population-based, Nested Case-control Study.
Recent controversies on the safety profiles of opioids and paracetamol (acetaminophen) have led to changes in clinical guidance on osteoarthritis (OA) management. We studied the existing association between the use of different OA drug therapies and the risk for acute coronary events. A cohort of patients with clinically diagnosed OA (according to ICD-10 codes) was identified in the SIDIAP database. Within the cohort, cases with incident acute coronary events (acute myocardial infarction or unstable angina) between 2008 and 2012 were identified using ICD-10 codes and data from hospital admission. Controls were matched 3:1 to acute coronary event-free patients matched by sex, age (±5 years), geographic area, and years since OA diagnosis (±2 years). Linked pharmacy dispensation data were used for assessing exposure to drug therapies. Multivariate conditional logistic regression models were fitted to estimate adjusted odds ratios of acute coronary events. Totals of 5663 cases and 16,989 controls were studied. Previous morbidity and cardiovascular risk were higher in cases than in controls, with no significant differences in type or number of joints with OA. Multivariate adjusted analyses showed increased risks (odds ratio; 95% CI) related to the use of diclofenac (1.16; 1.06-1.27), naproxen (1.25; 1.04-1.48), and opioid analgesics (1.13; 1.03-1.24). No significant associations were observed with cyclooxygenase-2 selective NSAIDs, topical NSAIDs, glucosamine, chondroitin sulfate, paracetamol, or metamizole. In patients with clinically diagnosed OA, the use of nonselective NSAIDs or opioid analgesics is associated with an increased risk for acute coronary events. These risks should be considered when selecting treatments of OA in patients at high cardiovascular risk.


Glucose-6-phosphate dehydrogenase deficiency and the risk of malaria and other diseases in children in Kenya: a case-control and a cohort study.
The global prevalence of X-linked glucose-6-phosphate dehydrogenase (G6PD) deficiency is thought to be a result of selection by malaria, but epidemiological studies have yielded confusing results. We investigated the relationships between G6PD deficiency and both malaria and non-malarial illnesses among children in Kenya. We did this study in Kilifi County, Kenya, where the G6PD c.202T allele is the only significant cause of G6PD deficiency. We tested the associations between G6PD deficiency and severe and complicated Plasmodium falciparum malaria through a case-control study of 2220 case and 3940 control children. Cases were children aged younger than 14 years, who visited the high dependency ward of Kilifi County Hospital with severe malaria between March 1, 1998, and Feb 28, 2010. Controls were children aged between 3-12 months who were born within the same study area between August 2006, and September 2010. We assessed the association between G6PD deficiency and both uncomplicated malaria and other common diseases of childhood in a cohort study of 752 children aged younger than 10 years. Participants of this study were recruited from a representative sample of households within the Ngerenya and Chonyi areas of Kilifi County between Aug 1, 1998, and July 31, 2001. The primary outcome measure for the case-control study was the odds ratio for hospital admission with severe malaria (computed by logistic regression) while for the cohort study it was the incidence rate ratio for uncomplicated malaria and non-malaria illnesses (computed by Poisson regression), by G6PD deficiency category. 2863 (73%) children in the control group versus 1643 (74%) in the case group had the G6PD normal genotype, 639 (16%) versus 306 (14%) were girls heterozygous for G6PD c.202T, and 438 (11%) versus 271 (12%) children were either homozygous girls or hemizygous boys. Compared with boys and girls without G6PD deficiency, we found significant protection from severe malaria (odds ratio [OR] 0·82, 95% CI 0·70-0·97; p=0·020) among G6PD c.202T heterozygous girls but no evidence for protection among G6PD c.202T hemizygous boys and homozygous girls (OR 1·18, 0·99-1·40; p=0·056). Median follow-up for the mild disease cohort study was 2·24 years (IQR 2·22-2·85). G6PD c.202T had no effect on other common diseases of childhood in heterozygous girls (incidence rate ratio 0·98, 95% CI 0·86-1·11; p=0·82) or homozygous girls or hemizygous boys (0·93, 0·82-1·04; p=0·25), with the sole exception of a marginally significant increase in the incidence of helminth infections among heterozygous girls. Heterozygous girls might be the driving force for the positive selection of G6PD deficiency alleles. Further studies are needed to definitively establish the mechanisms by which G6PD deficiency confers an advantage against malaria in heterozygous individuals. Such studies could lead to the development of new treatments. Wellcome Trust, UK Medical Research Council, European Union, and Foundation for the National Institutes of Health (as part of the Bill & Melinda Gates Grand Challenges in Global Health Initiative).


Ginseng is useful to enhance cardiac contractility in animals.
Ginseng has been shown to be effective on cardiac dysfunction. Recent evidence has highlighted the mediation of peroxisome proliferator-activated receptors (PPARs) in cardiac function. Thus, we are interested to investigate the role of PPARδ in ginseng-induced modification of cardiac contractility. The isolated hearts in Langendorff apparatus and hemodynamic analysis in catheterized rats were applied to measure the actions of ginseng ex vivo and in vivo. In normal rats, ginseng enhanced cardiac contractility and hemodynamic dP/dt(max) significantly. Both actions were diminished by GSK0660 at a dose enough to block PPARδ. However, ginseng failed to modify heart rate at the same dose, although it did produce a mild increase in blood pressure. Data of intracellular calcium level and Western blotting analysis showed that both the PPARδ expression and troponin I phosphorylation were raised by ginseng in neonatal rat cardiomyocyte. Thus, we suggest that ginseng could enhance cardiac contractility through increased PPARδ expression in cardiac cells.


Adherence to Telemonitoring by Electronic Patient-Reported Outcome Measures in Patients with Chronic Diseases: A Systematic Review.
Background: Effective telemonitoring is possible through repetitive collection of electronic patient-reported outcome measures (ePROMs) in patients with chronic diseases. Low adherence to telemonitoring may have a negative impact on the effectiveness, but it is unknown which factors are associated with adherence to telemonitoring by ePROMs. The objective was to identify factors associated with adherence to telemonitoring by ePROMs in patients with chronic diseases. Methods: A systematic literature search was conducted in PubMed, Embase, PsycINFO and the Cochrane Library up to 8 June 2021. Eligibility criteria were: (1) interventional and cohort studies, (2) patients with a chronic disease, (3) repetitive ePROMs being used for telemonitoring, and (4) the study quantitatively investigating factors associated with adherence to telemonitoring by ePROMs. The Cochrane risk of bias tool and the risk of bias in nonrandomized studies of interventions were used to assess the risk of bias. An evidence synthesis was performed assigning to the results a strong, moderate, weak, inconclusive or an inconsistent level of evidence. Results: Five studies were included, one randomized controlled trial, two prospective uncontrolled studies and two retrospective cohort studies. A total of 15 factors potentially associated with adherence to telemonitoring by ePROMs were identified in the predominate studies of low quality. We found moderate-level evidence that sex is not associated with adherence. Some studies showed associations of the remaining factors with adherence, but the overall results were inconsistent or inconclusive. Conclusions: None of the 15 studied factors had conclusive evidence to be associated with adherence. Sex was, with moderate strength, not associated with adherence. The results were conflicting or indecisive, mainly due to the low number and low quality of studies. To optimize adherence to telemonitoring with ePROMs, mixed-method studies are needed.


Dynamics of tissue optics during laser heating of turbid media.
The dynamics of the optical behavior of tissue during the photothermal interaction of laser radiation with tissue could significantly affect the optimization of light doses for effective and safe applications of lasers in medicine. Characterization of the dynamics of tissue optics during laser heating was performed by means of simultaneous measurements of the total transmittance, diffuse reflectance, and surface temperature of fresh and thermally coagulated human skin and canine aorta during long-pulsed Nd:YAG laser heating with a double integrating-sphere system and an infrared camera. Thermally induced changes in the optical properties of tissue caused a decrease in the total transmittance and an increase in the diffuse reflectance of both fresh and precoagulated skin and aorta samples. For fresh tissue, these changes were primarily reversible until photocoagulation occurred, then both the reversible, as well as the irreversible, changes were observed. However, for precoagulated tissue the reversible changes in the optical properties were dominant, whereas the irreversible changes were insignificant. Results from this study indicate the existence of the nonlinear behavior in the optics of turbid biological media during pulsed laser heating. Possible mechanisms responsible for this nonlinear optical behavior are discussed.


Sugar Intake Elicits Intelligent Searching Behavior in Flies and Honey Bees.
We present a comparison of the sugar-elicited search behavior in Drosophila melanogaster and Apis mellifera. In both species, intake of sugar-water elicits a complex of searching responses. The most obvious response was an increase in turning frequency. However, we also found that flies and honey bees returned to the location of the sugar drop. They even returned to the food location when we prevented them from using visual and chemosensory cues. Analyses of the recorded trajectories indicated that flies and bees use two mechanisms, a locomotor pattern involving an increased turning frequency and path integration to increase the probability to stay close or even return to the sugar drop location. However, evidence for the use of path integration in honey bees was less clear. In general, walking trajectories of honey bees showed a higher degree of curvature and were more spacious; two characters which likely masked evidence for the use of path integration in our experiments. Visual cues, i.e., a black dot, presented underneath the sugar drop made flies and honey bees stay closer to the starting point of the search. In honey bees, vertical black columns close to the sugar drop increased the probability to visit similar cues in the vicinity. An additional one trial learning experiment suggested that the intake of sugar-water likely has the potential to initiate an associative learning process. Together, our experiments indicate that the sugar-elicited local search is more complex than previously assumed. Most importantly, this local search behavior appeared to exhibit major behavioral capabilities of large-scale navigation. Thus, we propose that sugar-elicited search behavior has the potential to become a fruitful behavioral paradigm to identify neural and molecular mechanisms involved in general mechanisms of navigation.


Reference pricing of pharmaceuticals.
We consider a therapeutic market with potentially three pharmaceutical firms. Two of the firms offer horizontally differentiated brand-name drugs. One of the brand-name drugs is a new treatment under patent protection that will be introduced if the profits are sufficient to cover the entry costs. The other brand-name drug has already lost its patent and faces competition from a third firm offering a generic version perceived to be of lower quality. This model allows us to compare generic reference pricing (GRP), therapeutic reference pricing (TRP), and no reference pricing (NRP). We show that competition is strongest under TRP, resulting in the lowest drug prices (and medical expenditures). However, TRP also provides the lowest profits to the patent-holding firm, making entry of the new drug treatment least likely. Surprisingly, we find that GRP distorts drug choices most, exposing patients to higher health risks.


Selecting measures of emotional and behavioral disorders of childhood for use in general populations.
This paper puts forward suggestions for assessing the suitability of existing measures of emotional and behavioral disorders of childhood for use in general populations. Specific attention is focused on the definition of emotional and behavioral disorder, measurement approaches and guidelines for choosing which disorders to study. The measurement criteria under review include acceptability, applicability, procedural adequacy, reliability and validity. These criteria are applied to seven instruments previously described as suitable for epidemiological and clinical research. Among these instruments, the ones developed by Rutter, Achenbach and Quay best meet the criteria and show the most promise of being useful in general populations. Among research priorities for the future, the foremost should include the specification of rules of evidence for establishing the validity of new measures of emotional and behavioral disorder.


A statistical method for studying correlated rare events and their risk factors.
Longitudinal studies of rare events such as cervical high-grade lesions or colorectal polyps that can recur often involve correlated binary data. Risk factor for these events cannot be reliably examined using conventional statistical methods. For example, logistic regression models that incorporate generalized estimating equations often fail to converge or provide inaccurate results when analyzing data of this type. Although exact methods have been reported, they are complex and computationally difficult. The current paper proposes a mathematically straightforward and easy-to-use two-step approach involving (i) an additive model to measure associations between a rare or uncommon correlated binary event and potential risk factors and (ii) a permutation test to estimate the statistical significance of these associations. Simulation studies showed that the proposed method reliably tests and accurately estimates the associations of exposure with correlated binary rare events. This method was then applied to a longitudinal study of human leukocyte antigen (HLA) genotype and risk of cervical high grade squamous intraepithelial lesions (HSIL) among HIV-infected and HIV-uninfected women. Results showed statistically significant associations of two HLA alleles among HIV-negative but not HIV-positive women, suggesting that immune status may modify the HLA and cervical HSIL association. Overall, the proposed method avoids model nonconvergence problems and provides a computationally simple, accurate, and powerful approach for the analysis of risk factor associations with rare/uncommon correlated binary events.


Targeted cytosine deaminase-uracil phosphoribosyl transferase suicide gene therapy induces small cell lung cancer-specific cytotoxicity and tumor growth delay.
Small cell lung cancer (SCLC) is a highly malignant cancer for which there is no curable treatment. Novel therapies are therefore in great demand. In the present study we investigated the therapeutic effect of transcriptionally targeted suicide gene therapy for SCLC based on the yeast cytosine deaminase (YCD) gene alone or fused with the yeast uracil phosphoribosyl transferase (YUPRT) gene followed by administration of 5-fluorocytosine (5-FC) prodrug. The YCD gene or the YCD-YUPRT gene was placed under regulation of the SCLC-specific promoter insulinoma-associated 1 (INSM1). Therapeutic effect was evaluated in vitro in SCLC cell lines and in vivo in SCLC xenografted nude mice using the nonviral nanoparticle DOTAP/cholesterol for transgene delivery. INSM1-YCD/5-FC and INSM1-YCD-YUPRT/5-FC therapy induced high cytotoxicity in a range of SCLC cell lines. The highest therapeutic effect was obtained from the YCD-YUPRT fusion gene strategy. No cytotoxicity was induced after treatment of cell lines of other origin than SCLC. In addition the INSM1-YCD-YUPRT/5-FC therapy was superior to an established suicide gene system consisting of the herpes simplex virus thymidine kinase (HSVTK) gene and the prodrug ganciclovir. The superior effect was in part due to massive bystander cytotoxicity of YCD-YUPRT-produced toxins. Finally, INSM1-YCD-YUPRT/5-FC therapy induced significant tumor growth delay in SCLC xenografts compared with control-treated xenografts. The current study is the first to test cytosine deaminase-based suicide gene therapy for SCLC and the first to show an antitumor effect from the delivery of suicide gene therapeutics for SCLC in vivo.