Multilabel Acoustic Event Classification Using Real-World Urban Data and Physical Redundancy of Sensors.
Many people living in urban environments nowadays are overexposed to noise, which results in adverse effects on their health. Thus, urban sound monitoring has emerged as a powerful tool that might enable public administrations to automatically identify and quantify noise pollution. Therefore, identifying multiple and simultaneous acoustic sources in these environments in a reliable and cost-effective way has emerged as a hot research topic. The purpose of this paper is to propose a two-stage classifier able to identify, in real time, a set of up to 21 urban acoustic events that may occur simultaneously (i.e., multilabel), taking advantage of physical redundancy in acoustic sensors from a wireless acoustic sensors network. The first stage of the proposed system consists of a multilabel deep neural network that makes a classification for each 4-s window. The second stage intelligently aggregates the classification results from the first stage of four neighboring nodes to determine the final classification result. Conducted experiments with real-world data and up to three different computing devices show that the system is able to provide classification results in less than 1 s and that it has good performance when classifying the most common events from the dataset. The results of this research may help civic organisations to obtain actionable noise monitoring information from automatic systems.


Observation of phase noise reduction in photonically synthesized sub-THz signals using a passively mode-locked laser diode and highly selective optical filtering.
A Continuous Wave (CW) sub-THz photonic synthesis setup based on a single Passively Mode-Locked Laser Diode (PMLLD) acting as a monolithic Optical Frequency Comb Generator (OFCG) and highly selective optical filtering has been implemented to evaluate the phase noise performance of the generated sub-THz signals. The analysis of the synthesized sub-THz signals up to 120 GHz gives as a result an effective reduction of the electrical linewidth when compared to direct harmonic generation that begins at 50 GHz and becomes greater as the frequency increases. The phase noise reduction offered by the setup, along with its integration potential, cost and bandwidth, make it a promising candidate to the development of an integrated and high performance low phase noise local oscillator in the sub-THz range.


Perspective taking and theory of mind in hide and seek.
Does theory of mind play a significant role in where people choose to hide an item or where they search for an item that has been hidden? Adapting Anderson's "Hide-Find Paradigm" Anderson et al. (Action, Perception and Performance, 76, 907-913, 2014) participants viewed homogenous or popout visual arrays on a touchscreen table. Their task was to indicate where in the array they would hide an item, or to search for an item that had been hidden, by either a friend or a foe. Critically, participants believed that their sitting location at the touchtable was the same as-or opposite to-their partner's location. Replicating Anderson et al., participants tended to (1) select items nearer to themselves on homogenous displays, and this bias was stronger for a friend than foe; and (2) select popout items, and again, more for a friend than foe. These biases were observed only when participants believed that they shared the same physical perspective as their partner. Collectively, the data indicate that theory of mind plays a significant role in hiding and finding, and demonstrate that the hide-find paradigm is a powerful tool for investigating theory of mind in adults.


Factors influencing prescribing behaviour of physicians in Greece and Cyprus: results from a questionnaire based survey.
Over the past few decades, drug and overall healthcare expenditure have risen rapidly in most countries. The present study investigates the attitudes and the factors which influence physician prescribing decisions and practice in Greece and Cyprus. A postal questionnaire was developed by researchers at the Department of Health Economics at the National School of Public Health in Greece, specifically for the purposes of the study. This was then administered to a sample of 1,463 physicians in Greece and 240 physicians in Cyprus, stratified by sex, specialty and geographic region. The response rate was 82.3% in Greece and 80.4% in Cyprus. There were similarities but also many differences between the countries. Clinical effectiveness is the most important factor considered in drug prescription choice in both countries. Greek physicians were significantly more likely to take additional criteria under consideration, such as the drug form and recommended daily dose and the individual patient preferences. The list of main sources of information for physicians includes: peer-reviewed medical journals, medical textbooks, proceedings of conferences and pharmaceutical sales representatives. Only half of prescribers considered the cost carried by their patients. The majority of doctors in both countries agreed that the effectiveness, safety and efficacy of generic drugs may not be excellent but it is acceptable. However, only Cypriot physicians actually prescribe them. Physicians believe that new drugs are not always better and their higher prices are not necessarily justified. Finally, doctors get information regarding adverse drug reactions primarily from the National Organisation for Medicines. However, it is notable that the majority of them do not inform the authorities on such reactions. The present study highlights the attitudes and the factors influencing physician behaviour in the two countries and may be used for developing policies to improve their choices and hence to increase clinical and economic effectiveness and efficiency.


Wild isolates of Plasmodium falciparum show extensive polymorphism in T cell epitopes of the circumsporozoite protein.
Variation in the immunodominant T cell epitopes Th2R and Th3R of the Plasmodium falciparum circumsporozoite protein has been analysed from Gambian clinical isolates using the polymerase chain reaction. The degree of polymorphism in these epitopes is more extensive than that found in several geographically diverse laboratory isolates. These findings strongly suggest that it will not be feasible to include all variants in a polyvalent subunit sporozoite vaccine.


Different Narrow-Band Light Ranges Alter Plant Secondary Metabolism and Plant Defense Response to Aphids.
Light of different wavelengths affects various physiological processes in plants. Short-wavelength radiation (like UV) can activate defense pathways in plants and enhance the biosynthesis of secondary metabolites (such as flavonoids and glucosinolates) responsible for resistance against certain herbivorous insects. The intensity of light-induced, metabolite-based resistance is plant- and insect species-specific and depends on herbivore feeding guild and specialization. In this study, broccoli (Brassica oleracea var. italica) plants were grown for 4 weeks in a climate chamber under conventional fluorescent tubes and were additionally treated with UV-B (310 nm), UV-A (365 or 385 nm), or violet (420 nm) light generated with UV-B tubes or light-emitting diodes (LEDs). The objective was to determine the influence of narrow bandwidths of light (from UV-B to violet) on plant secondary metabolism and on the performance of the cabbage aphid Brevicoryne brassicae (a specialist) and the green peach aphid Myzus persicae (a generalist). Among flavonol glycosides, specific quercetin and kaempferol glycosides increased markedly under UV-B, while among glucosinolates only 4-methoxy-3-indolylmethyl showed a 2-fold increase in plants exposed to UV-B and UV-A. The concentration of 3-indolylmethyl glucosinolate in broccoli plants increased with UV-B treatment. Brevicoryne brassicae adult weights and fecundity were lower on UV-B treated plants compared to UV-A or violet light-treated plants. Adult weights and fecundity of M. persicae were increased under UV-B and UV-A treatments. When specific light wavelengths are used to induce metabolic changes in plants, the specificity of the induced effects on herbivores should be considered.


Spontaneous Internalization of Cell Penetrating Peptide-Modified Nanowires into Primary Neurons.
Semiconductor nanowire (NW) devices that can address intracellular electrophysiological events with high sensitivity and spatial resolution are emerging as key tools in nanobioelectronics. Intracellular delivery of NWs without compromising cellular integrity and metabolic activity has, however, proven difficult without external mechanical forces or electrical pulses. Here, we introduce a biomimetic approach in which a cell penetrating peptide, the trans-activating transcriptional activator (TAT) from human immunodeficiency virus 1, is linked to the surface of Si NWs to facilitate spontaneous internalization of NWs into primary neuronal cells. Confocal microscopy imaging studies at fixed time points demonstrate that TAT-conjugated NWs (TAT-NWs) are fully internalized into mouse hippocampal neurons, and quantitative image analyses reveal an ca. 15% internalization efficiency. In addition, live cell dynamic imaging of NW internalization shows that NW penetration begins within 10-20 min after binding to the membrane and that NWs become fully internalized within 30-40 min. The generality of cell penetrating peptide modification method is further demonstrated by internalization of TAT-NWs into primary dorsal root ganglion (DRG) neurons.


Deacetylated GM3 promotes uPAR-associated membrane molecular complex to activate p38 MAPK in metastatic melanoma.
GM3, the simplest ganglioside, regulates cell proliferation, migration, and invasion by influencing cell signaling at the membrane level. Although the classic N-acetylated form of GM3 (NeuAcLacCer) is commonly expressed and has been well studied, deacetylated GM3 (NeuNH2LacCer, d-GM3) has been poorly investigated, despite its presence in metastatic tumors but not in noninvasive melanomas or benign nevi. We have recently found that d-GM3 stimulates cell migration and invasion by activating urokinase plasminogen activator receptor (uPAR) signaling to augment matrix metalloproteinase-2 (MMP-2) function. However, the mechanisms by which d-GM3/uPAR increase MMP-2 expression and activation are not clear. By modifying the expression of d-GM3 genetically and biochemically, we found that decreasing d-GM3 expression inhibits, whereas overexpressing d-GM3 stimulates, p38 mitogen-activated protein kinase (MAPK) activity to influence MMP-2 expression and activation. p38 MAPK (p38) activation requires the formation of a membrane complex that contains uPAR, caveolin-1, and integrin α5β1 in membrane lipid rafts. In addition, knocking down or inhibiting focal adhesion kinase (FAK), phosphoinositide 3-kinase (PI3K), or Src kinase significantly reduces d-GM3-induced p38 phosphorylation and activation. Taken together, these results suggest that d-GM3 enhances the metastatic phenotype by activating p38 signaling through uPAR/integrin signaling with FAK, PI3K, and Src kinase as intermediates. Elucidation of the mechanisms by which d-GM3, a newly discovered, potential biomarker of metastatic melanomas, promotes cell metastasis will help us to understand the function of d-GM3 in metastatic melanomas and may lead to novel GM3-based cancer therapies.


Oxycodone as a component of multimodal analgesia for lactating mothers after Caesarean section: relationships between maternal plasma, breast milk and neonatal plasma levels.
Oxycodone has become popular for post-Caesarean section (CS) analgesia yet it is not currently recommended for use in breast-feeding mothers because of limited information on its excretion into breast milk. To investigate the relationship between maternal ingestion of oxycodone after CS and the resultant maternal plasma, breast milk and neonatal plasma drug levels up to 72-h post-partum. Fifty breast-feeding mothers taking oxycodone had blood and breast milk samples analysed for oxycodone levels at 24 h intervals after CS. Forty-one neonates had blood samples taken at 48 h. Oxycodone was detected in the milk of mothers who had taken any dose in a 24-h period, with significant correlation between maternal plasma and milk levels (R(2) = 0.81). The median milk:plasma (M:P) ratio for the same period was 3.2:1. Over the subsequent 48 h, the relationship between plasma and milk levels was less strong (R(2) = 0.59) and there was a larger range of M:P levels with evidence of persistence of oxycodone in the breast milk of some mothers. Oxycodone levels up to 168 ng/mL were detected in breast milk (20% > 100 ng/mL). Oxycodone was detected in the plasma of one infant. Oxycodone is concentrated in human breast milk up to 72-h post-partum. Breastfed infants may receive > 10% of a therapeutic infant dose. However, maternal oxycodone intake up to 72-h post-CS poses only minimal risk to the breast-feeding infant as low volumes of breast milk are ingested during this period.


Experimental evidence of 25-fs laser pulse distortion in singlet beam expanders.
We report the measurement of spatiotemporal distortions of an ultrashort pulse in singlet beam expanders. With a simple second-order autocorrelator the temporal broadening of the pulse from 23 to 40 fs, due to propagation time difference (PTD), is determined. The delay due to PTD between different parts of the beam is also measured. This effect was theoretically studied for the first time by Bor [J. Mod. Opt. 35, 1907 (1988)]. These experimental results are in good agreement with the calculations of a dedicated three-dimensional ray-tracing program developed to simulate the spatial and temporal transformation of femtosecond pulses in optical systems.


Encouraging breastfeeding: A relational perspective.
Despite the WHO recommendations that babies should be breastfed exclusively for six months and thereafter for up to two years and beyond this pattern of feeding is far from the global norm. Although breastfeeding is triggered through biological mechanisms which have not changed with time, the perception of breastfeeding as a phenomenon is variable, as it not only reflects cultural values of motherhood but is also negotiable from the perspective of the individual. This paper argues that relationships are central to encouraging breastfeeding at an organisational, family and staff-parent level. This shifts our conceptualisations away from the primary focus of breastfeeding as nutrition which, in turn, removes the notion of breastfeeding as a productive process, prone to problems and failure.


Offering results to participants in a diabetes survey: effects on survey response rates.
There are many reasons why an investigator may choose to share results with survey respondents; however, the practice is not universal. Moreover, while there is some evidence that the practice increases response rates, it is of limited generalizability. The aim of this study was to determine both the impact on survey response rates of offering study results to participants, and the extent to which surveyed individuals with diabetes mellitus want results reported back from a postal questionnaire. In November-December 2009, we surveyed 4796 randomly selected individuals from a US Midwestern health system diabetes registry. Half of the sample was randomized to receive an offer of survey results as an incentive. Response rates were compared across the two groups. Within the group offered results, we compared those that requested them with those that declined with respect to demographic characteristics, self-reported diabetes severity, and characterization of care received for diabetes. The overall response rate was 42.8% (n = 2055). Offering survey results did not impact response rates overall or within specific subpopulations. Of those randomized to the offer of results, 62.1% requested the results (n = 618). Requests for results differed by educational attainment and the rating of diabetes care as poor, although only education remained a significant predictor in multivariate analysis. There were no differences in rates of requests by disease severity or overall health status. Offering survey results to potential respondents did not increase the likelihood of response among a patient population with diabetes. Of those that were offered results and returned the survey, 62.1% requested that they receive study results, indicating a potentially important educational opportunity. However, as result requests were driven more by educational attainment than by health status, investigators may want to send results to everyone, not just those that request them.


γ-Synuclein antibodies have neuroprotective potential on neuroretinal cells via proteins of the mitochondrial apoptosis pathway.
The family of synuclein proteins (α, β and γ) are related to neurodegenerative disease e.g. Parkinson disease and Morbus Alzheimer. Additionally, a connection between γ-synuclein and glaucoma, a neurodegenerative disease characterized by a progressive loss of retinal ganglion cells, which finally leads to blindness, exists. The reason for the development of glaucoma is still unknown. Recent studies evaluating the participation of immunological components, demonstrate complex changed antibody reactivities in glaucoma patients in comparison to healthy people, showing not only up-regulations (e.g. alpha-fodrin antibody) but also down-regulations (e.g. γ-synuclein antibody) of antibodies in glaucoma patients. Up-regulated antibodies could be auto-aggressive, but the role of down-regulated antibodies is still unclear. Previous studies show a significant influence of the serum and the antibodies of glaucoma patients on protein expression profiles of neuroretinal cells. The aim of this study was to investigate the effect of γ-synuclein antibody on the viability and reactive oxygen species levels of a neuroretinal cell line (RGC-5) as well as their interaction with cellular proteins. We found a protective effect of γ-synuclein antibody resulting in an increased viability (up to 15%) and decreased reactive oxygen species levels (up to -12%) of glutamate and oxidative stressed RGC-5. These can be traced back to anti-apoptotic altered protein expressions in the mitochondrial apoptosis pathway indicated by mass spectrometry and validated by microarray analysis such as active caspase 3, bcl-2 associated-x-protein, S100A4, voltage-dependent anion channel, extracellular-signal-regulated-kinase (down-regulated) and baculoviral IAP repeat-containing protein 6, phosphorylated extracellular-signal-regulated-kinase (up-regulated). These changed protein expression are triggered by the γ-synuclein antibody internalization of RGC-5 we could see in immunohistochemical stainings. These findings let us assume a novel physiological function of γ-synuclein antibodies and give insights in the role of autoantibodies in glaucoma. We hypothesize that the down-regulation of autoantibodies found in glaucoma patients lead to a loss of protective autoimmunity.


Radiolabeled antibodies in prostate cancer: a case study showing the effect of host immunity on antibody bio-distribution.
Human tumors xenografted in immunodeficient mice are crucial models in nuclear medicine to evaluate the effectiveness of candidate diagnostic and therapeutic compounds. However, little attention has been focused on the biological profile of the host model and its potential effects on the bio-distribution and tumor targeting of the tracer compound under study. We specifically investigated the dissimilarity in bio-distribution of (111)In-DTPA-5A10, which targets free prostate specific antigen (fPSA), in two animal models. In vivo bio-distribution studies of (111)In-DTPA-5A10 were performed in immunodeficient BALB/c-nu or NMRI-nu mice with subcutaneous (s.c.) LNCaP tumors. Targeting-specificity of the tracer was assessed by quantifying the uptake in (a) mice with s.c. xenografts of PSA-negative DU145 cells as well as (b) BALB/c-nu or NMRI-nu mice co-injected with an excess of non-labeled 5A10. Finally, the effect of neonatal Fc-receptor (FcRn) inhibition on the bio-distribution of the conjugate was studied by saturating FcRn-binding capacity with nonspecific IgG1. The inherent biological attributes of the mouse model substantially influenced the bio-distribution and pharmacokinetics of (111)In-DTPA-5A10. With LNCaP xenografts in BALB/c-nu mice (with intact B and NK cells but with deficient T cells) versus NMRI-nu mice (with intact B cells, increased NK cells and absent T cells), we observed a significantly higher hepatic accumulation (26 ± 3.9 versus 3.5 ± 0.4%IA/g respectively), and concomitantly lower tumor uptake (25 ± 11 versus 52 ± 10%IA/g respectively) in BALB/c-nu mice. Inhibiting FcRn by administration of nonspecific IgG1 just prior to (111)In-DTPA-5A10 did not change tumor accumulation significantly. We demonstrated that the choice of immunodeficient mouse model importantly influence the bio-distribution of (111)In-DTPA-5A10. This study further highlighted important considerations in the evaluation of preclinical tracers, with respect to gaining information on their performance in the translational setting. Investigators utilizing xenograft models need to assess not only radiolabeling strategies, but also the host immunological status.


Host- rather than virus-related factors reduce health-related quality of life in hepatitis C virus infection.
Hepatitis C virus (HCV) infection is associated with decreased health-related quality of life (HRQOL). Although HCV has been suggested to directly impair neuropsychiatric functions, other factors may also play a role. In this cross-sectional study, we assessed the impact of various host-, disease- and virus-related factors on HRQOL in a large, unselected population of anti-HCV-positive subjects. All individuals (n = 1736) enrolled in the Swiss Hepatitis C Cohort Study (SCCS) were asked to complete the Short Form 36 (SF-36) and the Hospital Anxiety Depression Scale (HADS). 833 patients (48%) returned the questionnaires. Survey participants had significantly worse scores in both assessment instruments when compared to a general population. By multivariable analysis, reduced HRQOL (mental and physical summary scores of SF-36) was independently associated with income. In addition, a low physical summary score was associated with age and diabetes, whereas a low mental summary score was associated with intravenous drug use. HADS anxiety and depression scores were independently associated with income and intravenous drug use. In addition, HADS depression score was associated with diabetes. None of the SF-36 or HADS scores correlated with either the presence or the level of serum HCV RNA. In particular, SF-36 and HADS scores were comparable in 555 HCV RNA-positive and 262 HCV RNA-negative individuals. Anti-HCV-positive subjects have decreased HRQOL compared to controls. The magnitude of this decrease was clinically important for the SF-36 vitality score. Host and environmental, rather than viral factors, seem to impact on HRQOL level.


Development of the 'Extreme Demand Avoidance Questionnaire' (EDA-Q): preliminary observations on a trait measure for Pathological Demand Avoidance.
Pathological Demand Avoidance (PDA) is a term increasingly used in the United Kingdom to describe children who obsessively resist everyday demands, going to extreme lengths to avoid these. There is debate about its relationship with both autism spectrum disorder (ASD) and oppositional defiant disorder (ODD). Unlike ASD, children with PDA are said to use socially manipulative avoidance strategies; and unlike ODD, they resort to extreme, embarrassing or age-inappropriate behaviour. To date, there has been little research into PDA, and it remains contentious. Currently, there are no questionnaire instruments available to aid consistency in description. This study reports the development and preliminary validation of the 'Extreme Demand Avoidance Questionnaire' (EDA-Q), designed to quantify PDA traits based on parent-reported information. The validation study involved data from 326 parents of children aged 5-17 allocated to six groups based on information reported by parents about received diagnoses and behavioural difficulties: (a) typically developing children (N = 102), (b) children with ASD without disruptive behaviour (N = 36), (c) children with ASD with disruptive behaviour (N = 48), (d) children for whom PDA was suspected by parents (irrespective of other diagnoses) (N = 67), (e) children who had, according to parents, been identified as having PDA by a health professional, irrespective of other diagnoses (N = 50), and (6) disruptive behaviour or behavioural problems without suspected/identified ASD or PDA (N = 23). Although the Strengths and Difficulties Questionnaire (SDQ) did not differentiate PDA from those with ASD plus disruptive behaviour; score on the EDA-Q was significantly higher in PDA than all comparison groups. ROC analysis indicated good sensitivity (.80) and specificity (.85). Across all case groups, females scored higher than males on the EDA-Q. Separate cut-off scores were identified for older and younger age-groups. Our findings highlight the potential utility of the EDA-Q to assist the identification of this unusual profile for future research.


GP73-regulated oncolytic adenoviruses possess potent killing effect on human liver cancer stem-like cells.
Cancer stem cells (CSCs), also known as tumor-initiating cells, are highly metastatic, chemo-resistant and tumorigenic, and are critical for cancer development, maintenance and recurrence. Oncolytic adenovirus could targetedly kill CSCs and has been acted as a promising anticancer agent. Currently, a novel GP73-regulated oncolytic adenovirus GD55 was constructed to specifically treat liver cancer and exhibited obvious cytotoxicity effect. However, there remains to be confirmed that whether GD55 could effectively eliminate liver CSCs. We first utilized the suspension culture to enrich the liver CSCs-like cells, which acquires the properties of liver CSCs in self-renewal, differentiation, quiescence, chemo-resistance and tumorigenicity. The results indicated that GD55 elicited more significant cytotoxicity and stronger oncolytic effect in liver CSC-like cells compared to common oncolytic virus ZD55. Additionally, GD55 possessed the greater efficacy in suppressing the growth of implanted tumors derived from liver CSC-like cells than ZD55. Furthermore, GD55 induced remarkable apoptosis of liver CSC-like cells in vitro and in vivo, and inhibited the propogation of cells and angiogenesis in xenograft tumor tissues. Thus, GD55 may virtually represent an attractive therapeutic agent for targeting liver CSCs to achieve better clinical outcomes for HCC patients.


Targeted delivery of tumor necrosis factor-related apoptosis-inducing ligand to keratinocytes with a pemphigus mAb.
We determined the feasibility of using an anti-desmoglein (Dsg) mAb, Px44, to deliver a biologically active protein to keratinocytes. Recombinantly produced Px44-green fluorescent protein (GFP) injected into mice and skin organ culture delivered GFP to the cell surface of keratinocytes. We replaced GFP with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to produce Px44-TRAIL. We chose TRAIL as a biological model because it inhibits activated lymphocytes and causes apoptosis of hyperproliferative keratinocytes, features of various skin diseases. Px44-TRAIL formed a trimer, the biologically active form of TRAIL. Standard assays of TRAIL activity showed that Px44-TRAIL caused apoptosis of Jurkat cells and inhibited IFN-γ production by activated CD4+ T cells. Enzyme-linked immunoassay with Px44-TRAIL showed delivery of TRAIL to Dsg. Immunofluorescence with Px44-TRAIL incubated on skin sections and cultured keratinocytes or injected into mouse skin, human organ culture, or human xenografts detected TRAIL on keratinocytes. Px44-TRAIL caused apoptosis of the hyperproliferative, but not differentiating, cultured keratinocytes through binding to Dsg3. Foldon, a small trimerization domain, cloned into Px44-TRAIL maintained its stability and biological activity at 37° C for at least 48 hours. These data suggest that such targeted therapy is feasible and may be useful for hyperproliferative and inflamed skin diseases.


Variation in cytoplasmic microtubule organization and spindle length between the two forms of the dimorphic fungus Candida albicans.
Candida albicans is a dimorphic fungus capable of growing as a budding yeast and as a filamentous hypha. We have used the technique of immunofluorescence to study the changes in the microtubule cytoskeleton during the cell cycle in both growth forms. This approach has revealed the presence of an extensive system of microtubules, including cytoplasmic microtubules and a rod-like intranuclear spindle. We have provided a complete description of the arrangement of cytoplasmic and spindle microtubules at each phase of the yeast cell cycle. A novel and characteristic feature of the yeast phase of Candida is the presence of an array of short microtubules at the neck of the doublet cell. This neck-associated array (NAA), is apparently organized independently of the main microtubule-organizing centre, the spindle pole bodies, at late anaphase. Analysis of microtubule patterns in the hyphal state reveals that the general arrangements of microtubules are similar to those seen in the yeast phase. These patterns suggest a role for the cytoplasmic microtubules in the nuclear migration that occurs during hyphal growth. A major finding is that the mitotic spindle in hyphae is considerably longer (12-20 microns) than the spindle in yeast cells (7-8 microns). This may reflect the role of the hyphal mitotic spindle not only in nuclear division but also in the positioning of the daughter nuclei at the centres of hyphal compartments.


Use of Medicare claims data to estimate national trends in stroke incidence, 1985-1991.
Although stroke mortality has been declining in the United States for decades, recent trends in stroke incidence based on national data have not been described. We used Medicare hospitalization data to estimate national trends in the incidence of stroke among Americans aged 70 years or older, and we provide evidence of the validity of the estimate. We defined stroke as a principal diagnosis with International Classification of Diseases, 9th Revision, Clinical Modification codes 430 to 434 or 436 to 437. We excluded many recurrent cases from the analysis by eliminating persons hospitalized for stroke during the 5 years preceding the index stroke. We calculated annual adjusted incidence rates and examined trends graphically. We investigated the effect of different exclusion periods, trends in in-hospital mortality of stroke patients, and trends in out-of-hospital stroke mortality. We examined trends in relation to sex, race, and age. The estimated age- and sex-adjusted stroke incidence declined 9.5% from 1985 to 1989, then increased 3.3% to 1991. The pattern did not vary with the length of the exclusion period or when all listed diagnosis rather than principal diagnoses were used to identify stroke cases. Incidence trends resembled the overall trend for both men and women, for 5-year age groups, and for whites; the trend did not change for blacks. Stroke incidence declined steadily from 1985 to 1989 and then increased slightly to 1991. Several postulated potential sources of bias were investigated and found to be unlikely to account for the incidence decline, although some may have contributed to the subsequent incidence increase.


Epidemiology And Patterns Of Care At The End Of Life: Rising Complexity, Shifts In Care Patterns And Sites Of Death.
In 2015 an estimated 2.7 million people in the United States (1 percent of the population) died. Although decedents' illness experience varies substantially, important trends in care at the end of life are evident. To identify the most pressing health care policy issues related to end-of-life care, we present a comprehensive picture of the epidemiology and care patterns of people in the last stage of life. We identify three key trends in end-of-life care: increasing diversity in the primary diagnoses of decedents, increases in multimorbidity and illness complexity among people with terminal illnesses, and shifts in patterns of care at the end of life and in sites of death. This changing epidemiology of those in the last phase of life puts new pressures on the Medicare hospice benefit to ensure the availability of high-quality end-of-life care. In addition, health care policy makers must grapple with the fact that even with increasing use of hospice care, care intensity increases at the end of life. We highlight and discuss tensions that must be managed to ensure that high-quality care is accessible for people at the end of life.


Understanding change of direction ability in sport: a review of resistance training studies.
The ability to change direction while sprinting is considered essential for successful participation in most team and individual sports. It has traditionally been thought that strength and power development would enhance change of direction (COD) performance. The most common approach to quantifying these relationships, and to discovering determinants (physiological and mechanical) of COD performance, is with correlation analysis. There have not been any strength or power variables that significantly correlated with COD performance on a consistent basis and the magnitude of the correlations were, for the most part, small to moderate. The training studies in the literature that have utilized traditional strength and power training programmes, which involved exercises being performed bilaterally in the vertical direction (e.g. Olympic-style lifts, squats, deadlifts, plyometrics, vertical jumping), have mostly failed to elicit improvements in COD performance. Conversely, the training protocols reporting improvements in COD performance have utilized exercises that more closely mimic the demands of a COD, which include horizontal jump training (unilateral and bilateral), lateral jump training (unilateral and bilateral), loaded vertical jump training, sport-specific COD training and general COD training.


A functional role for ezrin during Shigella flexneri entry into epithelial cells.
Shigella flexneri is an enteroinvasive bacterium responsible for bacillary dysentery in humans. Bacterial entry into epithelial cells is a crucial step for the establishment of the infection. It is characterized by a transient reorganization of the host cell cytoskeleton at the site of bacterial interaction with the cell membrane, which leads to bacterial engulfment by a macropinocytic process. We show in this study that the membrane-cytoskeleton linker, ezrin, a member of the ERM (ezrin, radixin, moesin) family, plays an active role in the process of Shigella uptake. Ezrin is highly enriched in cellular protrusions induced by the bacterium and is found in close association with the plasma membrane. In addition, Shigella entry is significantly reduced in cells transfected with a dominant negative allele of ezrin with entry foci showing much shorter cellular protrusions. These results indicate that ezrin not only acts as a membrane-cytoskeleton linker, but may also mediate extension of cellular projections in the presence of signals such as those elicited by invading microorganisms.


Doxycycline potentiates antitumor effect of 5-aminolevulinic acid-mediated photodynamic therapy in malignant peripheral nerve sheath tumor cells.
Neurofibromatosis type 1 (NF1) is one of the most common neurocutaneous disorders. Some NF1 patients develop benign large plexiform neurofibroma(s) at birth, which can then transform into a malignant peripheral nerve sheath tumor (MPNST). There is no curative treatment for this rapidly progressive and easily metastatic neurofibrosarcoma. Photodynamic therapy (PDT) has been developed as an anti-cancer treatment, and 5-aminolevulinic (ALA) mediated PDT (ALA-PDT) has been used to treat cutaneous skin and oral neoplasms. Doxycycline, a tetracycline derivative, can substantially reduce the tumor burden in human and animal models, in addition to its antimicrobial effects. The purpose of this study was to evaluate the effect and to investigate the mechanism of action of combined doxycycline and ALA-PDT treatment of MPNST cells. An 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that the combination of ALA-PDT and doxycycline significantly reduce MPNST survival rate, compared to cells treated with each therapy alone. Isobologram analysis showed that the combined treatment had a synergistic effect. The increased cytotoxic activity could be seen by an increase in cellular protoporphyrin IX (PpIX) accumulation. Furthermore, we found that the higher retention of PpIX was mainly due to increasing ALA uptake, rather than activity changes of the enzymes porphobilinogen deaminase and ferrochelatase. The combined treatment inhibited tumor growth in different tumor cell lines, but not in normal human Schwann cells or fibroblasts. Similarly, a synergistic interaction was also found in cells treated with ALA-PDT combined with minocycline, but not tetracycline. In summary, doxycycline can potentiate the effect of ALA-PDT to kill tumor cells. This increased potency allows for a dose reduction of doxycycline and photodynamic radiation, reducing the occurrence of toxic side effects in vivo.


Cross-cultural assessment of the Self-Care of Chronic Illness Inventory: A psychometric evaluation.
Self-care refers to behaviors that individuals adopt to prevent or maintain the stability of an illness (self-care maintenance), to monitor signs and symptoms (self-care monitoring), and to respond to signs and symptoms of an illness exacerbation (self-care management). A generic measure of self-care, the Self-Care of Chronic Illness Inventory, based on the Theory of Self-Care of Chronic Illness, was developed for use in individuals with any number and type of chronic conditions. The current study investigated the measurement equivalence of the Self-Care of Chronic Illness Inventory in individuals from three different cultural groups. We were interested in determining if Italians, Swedes, and Americans interpret the measure in a conceptually similar way. This cross-sectional study enrolled 1629 patients, 784 recruited in Italy, 438 in Sweden and 407 in the United States. Self-care (self-care maintenance, self-care monitoring and self-care management) was measured with the Self-Care of Chronic Illness Inventory. A multi-group confirmatory factor analytic approach was used to assess the equivalence of the measures across the three countries. Configural, metric, scalar and strict invariance were tested through a series of nested models where increasingly stringent equality constraints were posited. Participants were mostly males (56.3%), older adults (69.8%) and had at least two chronic conditions. Results indicated that three out of four measurement equivalence levels were partially or totally supported in all three of the Self-Care of Chronic Illness Inventory scales. The partial scalar invariance level was reached for self-care maintenance [χ2(50) = 63.495, p = 0.095; RMSEA = 0.022, p = 0.999, 90% CI = 0.000 0.038; CFI = 0.981; TLI = 0.977; SRMR = 0.036], self-care monitoring [χ2(22) = 28.770, p = 0.095; RMSEA = 0.024, p = 0.978, 90% CI = 0.000 0.046; CFI = 0.996; TLI = 0.995; SRMR = 0.054], and self-care management [χ2(51) = 91.334, p = 0.001; RMSEA = 0.048, p = 0.576, 90% CI = 0.031 0.063; CFI = 0.949; TLI = 0.937; SRMR = 0.047] scales. These findings suggest that patients in the three countries used an identical cognitive framework or mental model when responding and used the 1-5 Likert response scale in an almost identical way, almost without bias. In spite of sociocultural differences, patients in these countries seem to share the same fundamental view of self-care. The results of the Self-Care of Chronic Illness Inventory will be comparable in these countries.


Planar cell polarity signaling in craniofacial development.
Out of the several signaling pathways controlling craniofacial development, the role of planar cell polarity (PCP) signaling is relatively poorly understood. This pathway, originally identified as a mechanism to maintain cell polarity within the epithelial cells of the Drosophila wing, has been linked to the proper development of a wide variety of tissues in vertebrates and invertebrates. While many of the pathway members are conserved, it appears that some of the members of the pathway act in a tissue-specific manner. Here, we discuss the role of this pathway in vertebrate craniofacial development, highlighting cranial neural crest migration, skull and palate formation and the role of non-traditional modulators of PCP signaling within this developmental process.


Involvement of twisted gastrulation in T cell-independent plasma cell production.
Bone morphogenetic protein (BMP) signaling is increasingly implicated in immune cell differentiation and function; however, direct in vivo evidence for such a role is still missing. In this article, we report that Twisted gastrulation (TWSG1), an extracellular regulator of BMP signaling, is expressed in activated B cells and regulates T-independent B cell responses in the mouse. Twsg1-deficient B cells mount stronger T-independent type 2 responses reflected as increased IgM levels and numbers of Ag-specific IgM-secreting cells. BCR stimulation of Twsg1-deficient B cells results in hyperproliferation, hyperresponsiveness, and decreased apoptosis, whereas TLR stimulation results in hyperproliferation and increased IgG3 production. These changes are reflected on the molecular level by increased transcription of Bcl-6, Pax5, and the BMP-responsive gene Id-2. The TWSG1 effects on B cells appear to be cell intrinsic, suggesting that Twsg1 expression in B cells serves to interpret BMP signals on a per-cell basis. In summary, our observations on the role of TWSG1 in B cell function is opening new paths toward the exploration of the role of BMP signaling in immunological processes.


Antioxidant and antimutagenic potential of Psidium guajava leaf extracts.
Fruits, vegetables and medicinal herbs rich in phenolics antioxidants contribute toward reduced risk of age-related diseases and cancer. In this study, Psidium guajava leaf extract was fractionated in various organic solvents viz. petroleum ether, benzene, ethyl acetate, ethanl and methanol and tested for their antioxidant and antimutagenic properties. Methanolic fraction showed maximum antioxidant activity comparable to ascorbic acid and butylated hydroxyl toluene (BHT) as tested by DPPH free radical scavenging, phosphomolybdenum, FRAP (Fe3 + reducing power) and CUPRAC (cupric ions (Cu2+) reducing ability) assays. The fraction was analyzed for antimutagenic activities against sodium azide (NaN3), methylmethane sulfonate (MMS), 2-aminofluorene (2AF) and benzo(a)pyrene (BP) in Ames Salmonella tester strains. The methanol extracted fraction at 80 μg/ml concentration inhibited above 70% mutagenicity. Further, phytochemical analysis of methanol fraction that was found to be most active revealed the presence of nine major compounds by gas chromatography-mass spectrometry (GC-MS). This data suggests that guava contains high amount of phenolics responsible for broad-spectrum antimutagenic and antioxidant properties in vitro and could be potential candidates to be explored as modern phytomedicine.


Congenital Thrombotic Thrombocytopenic Purpura: Atypical Presentation and New ADAMTS 13 Mutation in a Tunisian Child.
Congenital deficiency of ADAMTS13 is characterized by systemic platelet clumping, hemolytic anemia and multiorgan failure. Although, more than 100 mutations have been reported, atypical clinical presentation may be involved in diagnostic difficulties. A 2 year old Tunisian child presented with chronic thrombopenic purpura which failed to respond to corticosteroids. Hemolytic anemia with schistocytes, occurred ten months later, with no previous history of diarrhea or any neurological abnormality. Renal function and coagulation screening tests were normal. The count of platelet improved after fresh frozen infusion (FFP). Extensive investigations revealed a severe deficiency of ADAMTS 13 activity (level< 5%). Gene sequencing identified mutation in exon 18 of ADAMTS 13 gene. Prophylactic regimen with regular infusions of FFP was associated to favorable outcome. Early ADAMTS 13 activity testing and gene sequencing associated to precocious plasmatherapy are recommended to reduce morbidity and mortality of congenital TTP.


Increasing inhibition of hepatic protein secretion by colchicine during development.
Colchicine and other antimicrotubular drugs have been shown to impair plasma protein secretion by fetal rat liver at late gestation (day 21) markedly less than by the mature organ. In the present study, the effect of colchicine on plasma protein secretion by liver slices was determined at several times during rat development. Secretion of [14C]leucine-labeled albumin and [3H]glucosamine-labeled glycoproteins was only minimally impaired (20%) by colchicine (50 microM) on gestation day 19. Inhibition of protein secretion increased to about 40% just before birth and remained unchanged throughout the perinatal period. Inhibition increased thereafter until the maximum effect (75%) was first observed 28 days after birth. Studies in which [3H]-colchicine was used indicated that neither reduced colchicine levels in tissue nor reduced affinity of tubulin for colchicine caused the diminished impairment of secretion in immature liver. These findings suggest that participation of microtubules in liver plasma protein secretion is reduced during development and that full participation is delayed beyond the perinatal period in this species.


Preparation of Fluorescent Microcystin Derivatives by Direct Arginine Labelling and Their Biological Evaluation.
Microcystin is the most prevalent toxin produced by cyanobacteria and poses a severe threat to livestock, humans and entire ecosystems. We report the preparation of a series of fluorescent microcystin derivatives by direct arginine labelling of the unprotected peptides at the guanidinium side chain. This new method allows a simple late-stage diversification strategy for native peptides devoid of protecting groups under mild conditions. A series of fluorophores were conjugated to microcystin-LR in good to very good yield. The fluorescent probes displayed biological activity comparable to that of unlabelled microcystin, in both phosphatase inhibition assays and toxicity tests on the crustacean Thamnocephalus platyurus. In addition, we demonstrate that the fluorescent probes penetrated Huh7 cells. Whole-animal imaging was performed on T. platyurus: labelled compound was mainly observed in the digestive tract.


Modulation of hippocampal acetylcholine release and spontaneous alternation scores by intrahippocampal glucose injections.
Recent evidence indicates that systemic glucose treatment enhances memory while producing a corresponding increase in hippocampal acetylcholine (ACh) output. The present experiments examined whether unilateral intrahippocampal infusions of glucose would enhance spontaneous alternation performance and whether there would be a corresponding increase in ACh output in the ipsilateral and contralateral hippocampus. Extracellular ACh was assessed in samples collected at 12 min intervals using in vivo microdialysis with HPLC with electrochemical detection. Twelve minutes after a unilateral infusion of artificial cerebrospinal fluid (CSF) or glucose (6.6 mM), rats were tested in a cross maze for spontaneous alternation behavior with concurrent microdialysis collection. In two experiments, glucose infusions significantly increased alternation scores (67.5 and 59%) compared with CSF controls (42.4 and 39.5%, respectively). In both experiments, behavioral testing resulted in increased ACh output in the hippocampus. Glucose administration at the time of alternation tests enhanced ACh output beyond that of behavioral testing alone both ipsilateral (+93.8%) and contralateral (+85%) to the infusion site, as compared with ACh output (+36.1% and +55.5%) of CSF controls. Glucose infusions did not affect hippocampal ACh output in rats kept in a holding chamber. These results suggest that glucose may enhance alternation scores by modulating ACh release. The findings also indicate that unilateral glucose infusions increase hippocampal ACh output both ipsilateral and contralateral to the site of injection. Furthermore, glucose increased ACh output only during maze testing, suggesting that specific behavioral demands, perhaps requiring activation of cholinergic neurons, determine the efficacy of glucose in modulating ACh release.


TGF-β mediates proinflammatory seminal fluid signaling in human cervical epithelial cells.
The cervix is central to the female genital tract immune response to pathogens and foreign male Ags introduced at coitus. Seminal fluid profoundly influences cervical immune function, inducing proinflammatory cytokine synthesis and leukocyte recruitment. In this study, human Ect1 cervical epithelial cells and primary cervical cells were used to investigate agents in human seminal plasma that induce a proinflammatory response. TGF-β1, TGF-β2, and TGF-β3 are abundant in seminal plasma, and Affymetrix microarray revealed that TGF-β3 elicits changes in Ect1 cell expression of several proinflammatory cytokine and chemokine genes, replicating principal aspects of the Ect1 response to seminal plasma. The differentially expressed genes included several induced in the physiological response of the cervix to seminal fluid in vivo. Notably, all three TGF-β isoforms showed comparable ability to induce Ect1 cell expression of mRNA and protein for GM-CSF and IL-6, and TGF-β induced a similar IL-6 and GM-CSF response in primary cervical epithelial cells. TGF-β neutralizing Abs, receptor antagonists, and signaling inhibitors ablated seminal plasma induction of GM-CSF and IL-6, but did not alter IL-8, CCL2 (MCP-1), CCL20 (MIP-3α), or IL-1α production. Several other cytokines present in seminal plasma did not elicit Ect1 cell responses. These data identify all three TGF-β isoforms as key agents in seminal plasma that signal induction of proinflammatory cytokine synthesis in cervical cells. Our findings suggest that TGF-β in the male partner's seminal fluid may influence cervical immune function after coitus in women, and potentially be a determinant of fertility, as well as defense from infection.


Activation of Notch signaling in human colon adenocarcinoma.
Notch and Wnt signaling function together to regulate colonic progenitor cell division and differentiation. Studies in mice have also shown that Notch signaling is required for adenoma formation in response to elevated Wnt-pathway signaling that occurs in the APCMin mouse model of human adenomatous polyposis coli. We therefore used in situ hybridization to analyze expression of Notch ligands, receptors and fringe genes, as well as the Notch target gene, HES1, in human colorectal cancer (CRC). In a small cohort of tumors, JAGGED ligands, NOTCH1, LFNG and HES1 were expressed at levels similar to, or higher than, levels observed in the crypt. To explore the possibility that Notch signaling may play a quantitative role in human CRC we next analyzed HES1 mRNA expression in 130 tumors, each associated with outcome data. The vast majority of these tumors expressed HES1, although at varying levels. Absolute expression levels did not correlate with patient survival. These results establish that JAG ligands and NOTCH1, as well as Notch receptor activation are consistent features of human CRC and support the notion that many of these tumors, like the APCMin mouse, may respond to anti-Notch therapeutic regimes.


Cannibalism and Intraguild Predation Community Dynamics: Coexistence, Competitive Exclusion, and the Loss of Alternative Stable States.
Predators often exert strong top-down regulation of prey, but in many systems, juvenile predators must compete with their future prey for a shared resource. In such life-history intraguild predation (LHIGP) systems, prey can therefore also regulate the recruitment and thus population dynamics of their predator via competition. Theory predicts that such stage-structured systems exhibit a wide range of dynamics, including alternative stable states. Here we show that cannibalism is an exceedingly common interaction within natural LHIGP systems that determines what coexistence states are possible. Using a modeling approach that simulates a range of ontogenetic diet shift scenarios along a productivity gradient, we demonstrate that only if the predator is competitively dominant can cannibalism promote coexistence by allowing prey to persist. If the prey is competitively dominant, cannibalism instead results in competitive exclusion of the predator and the loss of potential alternative stable states. Further, predator exclusion occurs at low cannibalistic preference relative to empirical estimates and is consistent across LHIGP systems in which the predator undergoes a complete diet shift or diet broadening over ontogeny. Given that prey is frequently competitively dominant in natural systems, our results demonstrate that even weak cannibalism can inhibit predator persistence, prompting exploration of mechanisms that reconcile theory with the common occurrence of such interactions in nature.


Effect of Selective Heart Rate Slowing in Heart Failure With Preserved Ejection Fraction.
Heart failure with preserved ejection fraction (HFpEF) is associated with significant morbidity and mortality but is currently refractory to therapy. Despite limited evidence, heart rate reduction has been advocated, on the basis of physiological considerations, as a therapeutic strategy in HFpEF. We tested the hypothesis that heart rate reduction improves exercise capacity in HFpEF. We conducted a randomized, crossover study comparing selective heart rate reduction with the If blocker ivabradine at 7.5 mg twice daily versus placebo for 2 weeks each in 22 symptomatic patients with HFpEF who had objective evidence of exercise limitation (peak oxygen consumption at maximal exercise [o2 peak] <80% predicted for age and sex). The result was compared with 22 similarly treated matched asymptomatic hypertensive volunteers. The primary end point was the change in o2 peak. Secondary outcomes included tissue Doppler-derived E/e' at echocardiography, plasma brain natriuretic peptide, and quality-of-life scores. Ivabradine significantly reduced peak heart rate compared with placebo in the HFpEF (107 versus 129 bpm; P<0.0001) and hypertensive (127 versus 145 bpm; P=0.003) cohorts. Ivabradine compared with placebo significantly worsened the change in o2 peak in the HFpEF cohort (-2.1 versus 0.9 mL·kg(-1)·min(-1); P=0.003) and significantly reduced submaximal exercise capacity, as determined by the oxygen uptake efficiency slope. No significant effects on the secondary end points were discernable. Our observations bring into question the value of heart rate reduction with ivabradine for improving symptoms in a HFpEF population characterized by exercise limitation. URL: http://www.clinicaltrials.gov. Unique identifier: NCT02354573.


Development and Psychometric Evaluation of the IPV Internalized Stigma Scale.
Self-stigma is the internalization of widespread and negative attitudes around a devalued attribute. Being a victim of intimate partner violence (IPV) is a stigmatized identity, with IPV self-stigma is a potential barrier to help seeking. The lack of an IPV self-stigma scale limits current measurement of this latent trait; this study sought to fill this gap. We developed the IPV Internalized Self-stigma Scale (IPVIS) by revising existing self-stigma and devaluation/discrimination measures and adding new items to fill perceived gaps. Using an online survey, a diverse sample (N = 455, M = 39.51, SD = 12.03) with various relationship types (e.g., heterosexual, same-sex), IPV circumstances (e.g., male or female perpetrators/victims) and different gender and sexual identities was recruited. Participants first completed the item pool (44-items), followed by measures of IPV, anxiety, depression, social health, and self-efficacy with data analyzed using a multi-model approach (e.g., factor analysis, item response theory [IRT]). Factor analyses revealed one dominant factor; IRT analyses further refined the unidimensional item set. The final 11 items had high internal consistency, ω = .90, 95% CI [0.89, 0.91], and were highly informative with moderate to high discrimination levels. The IPVIS demonstrated measurement invariance by demographics, showing no differential item functioning by age groups, sex, residence (urban/suburban/rural), ethnicity (European/Caucasian vs. others), or relationship status (partnered/unpartnered). Initial validity examination revealed significant correlations between the IPVIS and related measures (e.g., depression, anxiety, social health). The IPVIS is suitable for research and has widespread clinical applicability. To the best of our knowledge, the IPVIS is the first scale developed that assesses IPV self-stigma inclusive of a diverse range of clients/participants, relationship types, and IPV circumstances.


Autosomal dominant polycystic kidney disease - a systemic disorder.
Autosomal dominant polycystic kidney disease [ADPKB] is one of the commonest genetic diseases. Apart from the involvement of the kidneys, several other organs, viz. the liver, the central nervous system, the pancreas, the spleen, the ovaries and the gut, amongst others, are also sometimes involved. This makes ADFKD more of a systemic rather than an isolated renal disorder. This becomes more so considering that the involvement of the other organs contribute significantly to the morbidity and mortality of ADPKD. This review looks at the pattern and prevalence of involvement of other organs, apart from the kidney in ADPKD.


Age, sex, and telomere dynamics in a long-lived seabird with male-biased parental care.
The examination of telomere dynamics is a recent technique in ecology for assessing physiological state and age-related traits from individuals of unknown age. Telomeres shorten with age in most species and are expected to reflect physiological state, reproductive investment, and chronological age. Loss of telomere length is used as an indicator of biological aging, as this detrimental deterioration is associated with lowered survival. Lifespan dimorphism and more rapid senescence in the larger, shorter-lived sex are predicted in species with sexual size dimorphism, however, little is known about the effects of behavioral dimorphism on senescence and life history traits in species with sexual monomorphism. Here we compare telomere dynamics of thick-billed murres (Urialomvia), a species with male-biased parental care, in two ways: 1) cross-sectionally in birds of known-age (0-28 years) from one colony and 2) longitudinally in birds from four colonies. Telomere dynamics are compared using three measures: the telomere restriction fragment (TRF), a lower window of TRF (TOE), and qPCR. All showed age-related shortening of telomeres, but the TRF measure also indicated that adult female murres have shorter telomere length than adult males, consistent with sex-specific patterns of ageing. Adult males had longer telomeres than adult females on all colonies examined, but chick telomere length did not differ by sex. Additionally, inter-annual telomere changes may be related to environmental conditions; birds from a potentially low quality colony lost telomeres, while those at more hospitable colonies maintained telomere length. We conclude that sex-specific patterns of telomere loss exist in the sexually monomorphic thick-billed murre but are likely to occur between fledging and recruitment. Longer telomeres in males may be related to their homogamous sex chromosomes (ZZ) or to selection for longer life in the care-giving sex. Environmental conditions appeared to be the primary drivers of annual changes in adult birds.


An interview with Paola Arlotta.
Paola Arlotta is a neurodevelopmental biologist based at the Harvard Department of Stem Cell and Regenerative Biology in Boston, MA, USA. Her lab studies the birth, differentiation and assembly of neuronal circuits in the cerebral cortex with the aim of developing novel therapies for degenerative and neuropsychiatric diseases. Paola has recently become an editor for Development, and we asked her about her research and career, and her recent efforts to support women in science.


Optimism and self-efficacy mediate the association between shyness and subjective well-being among Chinese working adults.
The aim of the current study was to investigate whether optimism and self-efficacy mediated the association between shyness and subjective well-being in a sample of Chinese working adults. Two hundred and eight participants completed the Revised Cheek and Buss Shyness Scale, Life Orientation Rest-Revised, Satisfaction with Life Scale, and Positive and Negative Affect Scale. Structural equation modeling results showed that optimism mediated the relationship between shyness and measures of subjective well-being (life satisfaction, positive and negative affect). Self-efficacy mediated the association between shyness and positive subjective well-being (life satisfaction and positive affect). These results suggest that optimism and self-efficacy play unique mediating roles in the relationship between shyness and subjective well-being. They also have important implications for the development of intervention programs aimed at promoting subjective well-being of Chinese working adults through enhancing self-efficacy and optimism.


The enduracidin biosynthetic gene cluster from Streptomyces fungicidicus.
The biosynthetic gene cluster for the 17 aa peptide antibiotic enduracidin has been cloned and sequenced from Streptomyces fungicidicus ATCC 21013. The 84 kb gene cluster contains 25 ORFs and is located within a 116 kb genetic locus that was fully sequenced. Targeted disruption of non-ribosomal peptide synthetase (NRPS) genes in the cluster abolished enduracidin production and confirmed function. The cluster includes four genes, endA-D, encoding two-, seven-, eight- and one-module NRPSs, respectively, and includes unique modules for the incorporation of citrulline and enduracididine. The NRPS organization generally follows the collinearity principle, and starts with a condensation domain (C domain) similar to those found in other lipopeptide systems for the coupling of an acyl group to the starting amino acid. The sixth module of EndB, corresponding to Thr(8), is missing an adenylation domain (A domain) and this module is presumed to be loaded in trans by the single module protein EndD. The most striking feature of the NRPS organization is the lack of epimerization domains (E domains) in light of the fact that the product has seven d-amino acid residues. Sequence analysis reveals that C domains following modules corresponding to d-amino acids belong to a unique subset of C domains able to catalyse both epimerization and condensation reactions. Other genes directing lipid modification and activation, and formation of the non-proteinogenic amino acids 4-hydroxyphenylglycine and enduracididine are readily identified, as are genes possibly involved in regulation of antibiotic biosynthesis and export. These findings provide the basis to further genetically manipulate and improve lipodepsipeptide antibiotics via combinatorial and chemical methods.


Reducing the Global Burden of Cardiovascular Disease, Part 2: Prevention and Treatment of Cardiovascular Disease.
In this second part of a 2-part series on the global burden of cardiovascular disease, we review the proven, effective approaches to the prevention and treatment of cardiovascular disease. We specifically review the management of acute cardiovascular diseases, including acute coronary syndromes and stroke; the care of cardiovascular disease in the ambulatory setting, including medical strategies for vascular disease, atrial fibrillation, and heart failure; surgical strategies for arterial revascularization, rheumatic and other valvular heart disease, and symptomatic bradyarrhythmia; and approaches to the prevention of cardiovascular disease, including lifestyle factors, blood pressure control, cholesterol-lowering, antithrombotic therapy, and fixed-dose combination therapy. We also discuss cardiovascular disease prevention in diabetes mellitus; digital health interventions; the importance of socioeconomic status and universal health coverage. We review building capacity for conduction cardiovascular intervention through strengthening healthcare systems, priority setting, and the role of cost effectiveness.


Binding of DNA to large fragment of DNA polymerase I: identification of strong and weak electrostatic forces and their biological implications.
Examination of the electrostatic potential of a modeled complex, consisting of the Klenow fragment of E. coli DNA polymerase I and DNA template-primer, suggested the presence of two distinct interacting regions. The one displaying a strong electropositive potential field is generated by side chains of basic amino acid pairs and is directed towards the major groove site in DNA. The second electrostatic potential field around DNA is somewhat weaker and appears to be exerted by a pair of vicinal side chains of acidic and basic amino acids. The distribution of charges in this manner appears well suited for the binding of enzyme to the template-primer required in the enzymatic synthesis of DNA.


Rasch analysis supports the use of the Pain Self-Efficacy Questionnaire.
The Pain Self-Efficacy Questionnaire (PSEQ) is used by physical therapists in clinical practice and in research. However, current understanding of the PSEQ's measurement properties is incomplete, and investigators cannot be confident that it provides unbiased information on patient self-efficacy. The aims of this study were: (1) to investigate the scale properties of the PSEQ using Rasch analysis and (2) to determine whether age, sex, pain intensity, pain duration, and pain-related disability bias function of the PSEQ. This was a retrospective study; data were obtained from 3 existing studies. Data were combined from more than 600 patients with low back pain of varying duration. Rasch analysis was used to evaluate targeting, category ordering, unidimensionality, person fit, internal consistency, and item bias. There was evidence of adequate category ordering, unidimensionality, and internal consistency of the PSEQ. Importantly, there was no evidence of item bias. The PSEQ did not adequately target the sample; instead, it targeted people with lower self-efficacy than this population. Item 7 was hardest for participants to endorse, showing excessive positive misfit to the Rasch model. Response strings of misfitting persons revealed older participants and those reporting high levels of disability. The individual items of the PSEQ can be validly summed to provide a score of self-efficacy that is robust to age, sex, pain intensity, pain duration, and disability. Although item 7 is the most problematic, it may provide important clinical information and requires further investigation before its exclusion. Although the PSEQ is commonly used with people with low back pain, of whom the sample in this study was representative, the results suggest it targets patients with lower self-efficacy than that observed in the current sample.


Using automated medical records for rapid identification of illness syndromes (syndromic surveillance): the example of lower respiratory infection.
Gaps in disease surveillance capacity, particularly for emerging infections and bioterrorist attack, highlight a need for efficient, real time identification of diseases. We studied automated records from 1996 through 1999 of approximately 250,000 health plan members in greater Boston. We identified 152,435 lower respiratory infection illness visits, comprising 106,670 episodes during 1,143,208 person-years. Three diagnoses, cough (ICD9CM 786.2), pneumonia not otherwise specified (ICD9CM 486) and acute bronchitis (ICD9CM 466.0) accounted for 91% of these visits, with expected age and sex distributions. Variation of weekly occurrences corresponded closely to national pneumonia and influenza mortality data. There was substantial variation in geographic location of the cases. This information complements existing surveillance programs by assessing the large majority of episodes of illness for which no etiologic agents are identified. Additional advantages include: a) sensitivity, uniformity and efficiency, since detection of events does not depend on clinicians' to actively report diagnoses, b) timeliness, the data are available within a day of the clinical event; and c) ease of integration into automated surveillance systems. These features facilitate early detection of conditions of public health importance, including regularly occurring events like seasonal respiratory illness, as well as unusual occurrences, such as a bioterrorist attack that first manifests as respiratory symptoms. These methods should also be applicable to other infectious and non-infectious conditions. Knowledge of disease patterns in real time may also help clinicians to manage patients, and assist health plan administrators in allocating resources efficiently.


[Outcomes of combined mitral valve repair surgery and aortic valve replacement in IKEM Praha].
We retrospectively analyzed long-term outcome of concomitant mitral valve repair and aortic valve replacement. From 1996 to 2009 we performed mitral valve plasty with aortic valve replacement in 50 patients. Clinical and echocardiographic data were obtained from computer database and hospital records. Missing data were obtained through mailed questionnaire. We evaluated hospital mortality, long-term survival, thromboembolic and hemorrhagic complications and TR of 3+ on follow up echocardiography. Four patients who had previously undergone aortic valve surgery were excluded from the study. Aortic valve pathology was stenosis in 21 patients, regurgitation in 20 and 4 patients presented with mixed aortic disease. The etiology of mitral regurgitation was rheumatic in 6, non-rheumatic in 31 and infective in 6 patients. Aortic valve was replaced with mechanical prosthesis in 22 (mean age 59) and tissue prosthesis in 24 (mean age 71) patients. Additional surgical procedure was performed in 26 patients. Follow-up was 94% complete, with a mean duration of 51 months. Hospital mortality was 13%. Two and five year survival was 79% and 64% respectively. We noted one case of retroperitoneal hemorrhage and one stroke. We recorded 9 (19.6%) patients with residual TR of more than 3+ grade on follow up echocardiography. Out of 9 patients with residual TR, 3 were operated for rheumatic and 6 for non-rheumatic mitral valve disease. One patients underwent successful mitral valve replacement with mechanical prosthesis, 3 died and 5 are treated expectantly. We conclude that concomitant mitral valve repair with aortic valve replacement has high hospital mortality, excellent long-term survival and low complication rate. The durability of mitral valve repair in patients with rheumatic mitral valve disease is limited and replacement, rather that repair should be considered in this patient group.


Therapeutic strategies targeting inflammation and immunity in atherosclerosis: how to proceed?
Atherosclerosis is a chronic inflammatory disease of the arterial wall, characterized by the formation of plaques containing lipid, connective tissue and immune cells in the intima of large and medium-sized arteries. Over the past three decades, a substantial reduction in cardiovascular mortality has been achieved largely through LDL-cholesterol-lowering regimes and therapies targeting other traditional risk factors for cardiovascular disease, such as hypertension, smoking, diabetes mellitus and obesity. However, the overall benefits of targeting these risk factors have stagnated, and a huge global burden of cardiovascular disease remains. The indispensable role of immunological components in the establishment and chronicity of atherosclerosis has come to the forefront as a clinical target, with proof-of-principle studies demonstrating the benefit and challenges of targeting inflammation and the immune system in cardiovascular disease. In this Review, we provide an overview of the role of the immune system in atherosclerosis by discussing findings from preclinical research and clinical trials. We also identify important challenges that need to be addressed to advance the field and for successful clinical translation, including patient selection, identification of responders and non-responders to immunotherapies, implementation of patient immunophenotyping and potential surrogate end points for vascular inflammation. Finally, we provide strategic guidance for the translation of novel targets of immunotherapy into improvements in patient outcomes.


Monoclonal antibodies to the alternative oxidase of higher plant mitochondria.
The higher plant mitochondrial electron transport chain contains, in addition to the cytochrome chain which terminates with cytochrome oxidase, an alternative pathway that terminates with an alternative oxidase. The alternative oxidase of Sauromatum guttatum Schott has recently been identified as a cluster of proteins with apparent M(r) of 37, 36, and 35 kilodaltons (kD). Monoclonal antibodies have now been prepared to these proteins and designated as AOA (binding all three proteins of the alternative oxidase cluster), AOU (binding the upper or 37 kD protein), and AOL (binding the lower or 36 and 35 kD proteins). All three antibodies bind to their respective alternative oxidase proteins whether the proteins are in their native or denatured states (as on protein blots). AOA and AOU inhibit alternative oxidase activity around 49%, whereas AOL inhibits activity only 14%. When coupled individually to Sepharose 4B, all three monoclonal resins were capable of retaining the entire cluster of alternative oxidase proteins, suggesting that these proteins are physically associated in some manner. The monoclonals were capable of binding similar mitochondrial proteins in a number of thermogenic and nonthermogenic species, indicating that they will be useful in characterizing and purifying the alternative oxidase of different systems. The ability of the monoclonal-Sepharose 4B resins to retain the cluster of previously identified alternative oxidase proteins, along with the inhibition of alternative oxidase activity by these monoclonals, supports the role of these proteins in constituting the alternative oxidase.


Implementation of semi-automated cloning and prokaryotic expression screening: the impact of SPINE.
The implementation of high-throughput (HTP) cloning and expression screening in Escherichia coli by 14 laboratories in the Structural Proteomics In Europe (SPINE) consortium is described. Cloning efficiencies of greater than 80% have been achieved for the three non-ligation-based cloning techniques used, namely Gateway, ligation-indendent cloning of PCR products (LIC-PCR) and In-Fusion, with LIC-PCR emerging as the most cost-effective. On average, two constructs have been made for each of the approximately 1700 protein targets selected by SPINE for protein production. Overall, HTP expression screening in E. coli has yielded 32% soluble constructs, with at least one for 70% of the targets. In addition to the implementation of HTP cloning and expression screening, the development of two novel technologies is described, namely library-based screening for soluble constructs and parallel small-scale high-density fermentation.


Anticoagulant treatment for subsegmental pulmonary embolism.
Acute pulmonary embolism (PE) is a common cause of death, accounting for 50,000 to 200,000 deaths annually. It is the third most common cause of mortality among the cardiovascular diseases, after coronary artery disease and stroke.The advent of multi-detector computed tomographic pulmonary angiography (CTPA) has allowed better assessment of PE regarding visualisation of the peripheral pulmonary arteries, increasing its rate of diagnosis. More cases of peripheral PEs, such as isolated subsegmental PE (SSPE) and incidental PE, have thereby been identified. These two conditions are usually found in patients with few or none of the classic PE symptoms such as haemoptysis or pleuritic pain, acute dyspnoea or circulatory collapse. However, in patients with reduced cardio-pulmonary (C/P) reserve the classic PE symptoms can be found with isolated SSPEs. Incidental SSPE is found casually in asymptomatic patients, usually by diagnostic imaging performed for other reasons (for example routine CT for cancer staging in oncologic patients).Traditionally, all PEs are anticoagulated in a similar manner independent of the location, number and size of the thrombi. It has been suggested that many patients with SSPE may be treated without benefit, increasing adverse events by possible unnecessary use of anticoagulants.Patients with isolated SSPE or incidental PE may have a more benign clinical presentation compared with those with proximal PEs. However, the clinical significance in patients and their prognosis have to be studied to evaluate whether anticoagulation therapy is required.This review is an update of a Cochrane systematic review first published in 2014. To assess the effectiveness and safety of anticoagulation therapy versus no intervention in patients with isolated subsegmental pulmonary embolism (SSPE) or incidental SSPE. The Cochrane Vascular Trials Search Co-ordinator searched the Specialised Register (last searched December 2015) and CENTRAL (2015, Issue 11). MEDLINE, EMBASE, LILACS and clinical trials databases were also searched. Randomised controlled trials of anticoagulation therapy versus no intervention in patients with SSPE or incidental SSPE. Two review authors inspected all citations to ensure reliable selection. We planned for two review authors to independently extract data and to assess the methodological quality of identified trials using the criteria recommended in the Cochrane Handbook for Systematic Reviews of Interventions. No studies were identified that met the inclusion criteria. There is no randomised controlled trial evidence for the effectiveness and safety of anticoagulation therapy versus no intervention in patients with isolated subsegmental pulmonary embolism (SSPE) or incidental SSPE, and therefore we can not draw any conclusions. Well-conducted research is required before informed practice decisions can be made.


Intraoperative hypotensive resuscitation for patients undergoing laparotomy or thoracotomy for trauma: Early termination of a randomized prospective clinical trial.
Hemorrhagic shock is responsible for one third of trauma related deaths. We hypothesized that intraoperative hypotensive resuscitation would improve survival for patients undergoing operative control of hemorrhage following penetrating trauma. Between July 1, 2007, and March 28, 2013, penetrating trauma patients aged 14 years to 45 years with a systolic blood pressure of 90 mm Hg or lower requiring laparotomy or thoracotomy for control of hemorrhage were randomized 1:1 based on a target minimum mean arterial pressure (MAP) of 50 mm Hg (experimental arm, LMAP) or 65 mm Hg (control arm, HMAP). Patients were followed up 30 days postoperatively. The primary outcome of mortality; secondary outcomes including stroke, myocardial infarction, renal failure, coagulopathy, and infection; and other clinical data were analyzed between study arms using univariate and Kaplan-Meier analyses. The trial enrolled 168 patients (86 LMAP, 82 HMAP patients) before early termination, in part because of clinical equipoise and futility. Injuries resulted from gunshot wounds (76%) and stab wounds (24%); 90% of the patients were male, and the median age was 31 years. Baseline vitals, laboratory results, and injury severity were similar between groups. Intraoperative MAP was 65.5 ± 11.6 mm Hg in the LMAP group and 69.1 ± 13.8 mm Hg in the HMAP group (p = 0.07). No significant survival advantage existed for the LMAP group at 30 days (p = 0.48) or 24 hours (p = 0.27). Secondary outcomes were similar for the LMAP and HMAP groups: acute myocardial infarction (1% vs. 2%), stroke (0% vs. 3%), any renal failure (15% vs. 12%), coagulopathy (28% vs. 29%), and infection (59% vs. 58%) (p > 0.05 for all). Acute renal injury occurred less often in the LMAP than in HMAP group (13% vs. 30%, p = 0.01). This study was unable to demonstrate that hypotensive resuscitation at a target MAP of 50 mm Hg could significantly improve 30-day mortality. Further study is necessary to fully realize the benefits of hypotensive resuscitation. Therapeutic study, level II.


A practical approach to nutritional screening and assessment in cirrhosis.
Malnutrition is one of the most common complications of cirrhosis, associated with an increased risk of morbidity and mortality. As a potentially modifiable condition, it is of particular importance to identify malnourished patients so that nutritional therapy can be instituted. Nutrition screening and assessment are infrequently performed in patients with cirrhosis. The reasons for this are multifactorial, including the absence of a validated "rapid" screening tool, multiple definitions of what constitutes malnutrition, and challenges with interpreting body composition and laboratory results in the setting of volume overload and liver dysfunction. This article summarizes the clinically relevant evidence and presents key issues, tools, and clinical options that are applicable to patients with cirrhosis. The definition, etiology, and clinically relevant outcomes associated with malnutrition are reviewed. Rapid nutritional screening is differentiated from more detailed nutritional assessment. Nutritional assessment in special populations, including women and the obese, and the role of inflammation are discussed. Multicenter studies using a common nutritional screening/assessment strategy are the next steps to fast-track adoption and implementation of nutrition-related evaluations into routine clinical practice. (Hepatology 2017;65:1044-1057).


A simple model of prefrontal cortex function in delayed-response tasks.
Both psychologists and neurobiologists have used delayed response (DR), AB, and delayed matching-to-sample (DMS) tasks as tools to study the functions of prefrontal cortex in primates and humans. We describe a simulation model that relates behavioral and electrophysiological-data relevant to these tasks into a minimal neural network. The inputs to the network are two visual objects and a positive or negative reinforcement signal. As the output, the network orients toward one of the two objects. We subdivide the architecture of the network into two levels, both of which embody constraints from neuroanatomy in a simplified form. Level 1 consists of a sensory-motor loop with modifiable synaptic weights and provides a capacity for grasping. Level 2 contains memory and rule-coding units and modulates the lower level 1. When level 1 only is simulated, the network fails to learn the tasks. The errors made by the network resemble those of young monkeys, infants, or adults with prefrontal lesions. In particular, the systematic AB error can be reproduced. With level 2 on top of level 1, the network acquires systematic rules of behavior by mere reinforcement and rapidly adapts to changes in the reinforcement schedule. Learning takes place by selection among a repertoire of possible rules. The properties of the model are discussed in terms of actual behavioral and physiological data, and several critical experimental predictions are presented. In particular, we address the issues of prefrontal functions, "systematicity" in neural networks, and "mental Darwinism."


Label-free and selective nonlinear fiber-optical biosensing.
We demonstrate that the inherent nonlinearity of a microstructured optical fiber (MOF) may be used to achieve label-free selective biosensing, thereby eliminating the need for post-processing of the fiber. This first nonlinear biosensor utilizes a change in the modulational instability (MI) gain spectrum (a shift of the Stokes- or anti-Stokes wavelength) caused by the selective capture of biomolecules by a sensor layer immobilised on the walls of the holes in the fiber. We find that such changes in the MI gain spectrum can be made detectable, and that engineering of the dispersion is important for optimizing the sensitivity. The nonlinear sensor shows a sensitivity of around 10.4 nm/nm, defined as the shift in resonance wavelength per nm biolayer, which is a factor of 7.5 higher than the hitherto only demonstrated label-free MOF biosensor.


Anomalous dispersion in atomic line filters applied for spatial frequency detection.
The anomalous dispersion of an atomic line filter near a resonant transition is exploited for full-field frequency measurements. The influence of the line shape function on the dispersion in atomic vapors near resonance and the possibilities to increase sensitivity are discussed. From the model-calculated absorption of iodine vapor at frequency-doubled Nd:YAG laser wavelengths, the corresponding refractive index is obtained through the Kramers-Kronig relations. Both variables are used to assess the performance of a iodine vapor cell as a dispersive element in an interferometric setup for Doppler frequency shift detection. With good agreement, the predicted sensitivity of the setup is compared to an experimental calibration. Observed discrepancies are attributed to the assumption of a Gaussian line shape in the absorption model. The full-field Doppler frequency measurement capacity of the technique is demonstrated in a rotating disk experiment, and the measurement performance is assessed.


An update on supported employment for people with severe mental illness.
This review examines the effectiveness of supported employment for people with severe mental illness. A comprehensive search was made for quantitative studies, primarily in the published literature. Seven descriptive studies, three surveys, one quasi-experimental study, and six experimental studies were found. All studies suggested significant gains in obtaining employment for persons enrolled in supported employment programs. In experimental studies, a mean of 58 percent of clients in supported employment programs achieved competitive employment, compared with 21 percent for control subjects, who typically received traditional vocational services. Employment outcomes relating to time employed and employment earnings also favored clients in supported employment over control subjects. No evidence was found that supported employment led to stress levels precipitating higher rehospitalization rates. Two features of many supported employment programs have the most empirical support: integration of mental health and vocational services within a single service team and the avoidance of preplacement training. Two other widely held principles-ongoing support and attention to client preferences-have not been systematically evaluated. Supported employment appears to be a promising approach for people with severe mental illness, but more studies are needed, with close attention to program implementation and long-term follow-up.


Community Health Workers in the United States: Challenges in Identifying, Surveying, and Supporting the Workforce.
Community health workers (CHWs) are members of a growing profession in the United States. Studying this dynamic labor force is challenging, in part because its members have more than 100 different job titles. The demand for timely, accurate information about CHWs is increasing as the profession gains recognition for its ability to improve health outcomes and reduce costs. Although numerous surveys of CHWs have been conducted, the field lacks well-delineated methods for gaining access to this hard-to-identify workforce. We outline methods for surveying CHWs and promising approaches to engage the workforce and other stakeholders in conducting local, state, and national studies. We also highlight successful strategies to overcome challenges in CHW surveys and future directions for surveying the field.


Inductive and ultrasonic multi-tier interface for low-power, deeply implantable medical devices.
We report the development of a novel multi-tier interface which enables the wireless, noninvasive transfer of sufficient amounts of power as well as the collection and transmission of data from low-power, deeply implantable analog sensors. The interface consists of an inductive coupling subsystem and an ultrasonic subsystem. The designed and experimentally verified inductive subsystem ensures that 5 W of power is transferred across 10 mm of air gap between a single pair of PCB spiral coils with an efficiency of 83% using our prototype CMOS logic gate-based driver circuit. The implemented ultrasonic subsystem, based on ultrasonic PZT ceramic discs driven in their low-frequency, radial/planar-excitation mode, further ensures that 29 μW of power is delivered 70 mm deeper inside a homogenous liquid environment-with no acoustic matching layer employed-with an efficiency of 1%. Overall system power consumption is 2.3 W. The implant is intermittently powered every 800 msec; charging a capacitor which provides sufficient power for a duration of ~ 18 msec; sufficient for an implant μC operating at a frequency of 500 KHz to transmit a nibble (4 bits) of digitized sensed data.


Review of the evidence for thresholds for DNA-Reactive and epigenetic experimental chemical carcinogens.
In the deliberations over many years on the question of thresholds for the carcinogenicity of chemicals, the dominant paradigm has been the linear no-threshold (LNT) model, derived from concepts formulated in radiation mutagenicity. Based on the analogy with radiation, the key mechanistic assumption underlying the assessment of the dose-effect of chemical-induced carcinogenicity has been that any dose, no matter how low, can lead to induction of mutations, which will result in some risk of neoplasia. The LNT assumption, however, was never well founded and, its application to chemical carcinogens, does not allow for differences in their disposition or mechanisms of action. These mechanisms include DNA-reactivity and epigenetic effects, resulting from very different properties of carcinogens, leading to different dose effects. This review of the research on dose effects of chemical carcinogens administered by repeat dosing for long duration reveals that only some experiments involving what are now recognized as DNA-reactive carcinogens yielded dose effects for induction of tumors which were consistent with the absence of a threshold (for 6/14 chemicals). None of these studies, however, included low doses documented not to produce genetic or other cellular toxicities that underlie carcinogenicity. Otherwise, most dose-effect experiments, including all with epigenetic agents (7), revealed no-observed-effect-levels for tumors, indicative of subthreshold doses. Based on highly informative experimental data, including relevant mechanistic data, it is concluded that no-effect-levels exist for both carcinogen-induced precursor effects and neoplasia. Accordingly, we conclude that, at non-toxic dosages, thresholds exist for the induction of experimental cancer by all types of carcinogens.


Association of chronic fatigue syndrome with premature telomere attrition.
Chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME), is a severely debilitating condition of unknown etiology. The symptoms and risk factors of ME/CFS share features of accelerated aging implicated in several diseases. Using telomere length as a marker, this study was performed to test the hypothesis that ME/CFS is associated with accelerated aging. Participant (n = 639) data came from the follow-up time point of the Georgia CFS surveillance study. Using the 1994 CFS Research Case Definition with questionnaire-based subscale thresholds for fatigue, function, and symptoms, participants were classified into four illness groups: CFS if all criteria were met (n = 64), CFS-X if CFS with exclusionary conditions (n = 77), ISF (insufficient symptoms/fatigue) if only some criteria were met regardless of exclusionary conditions (n = 302), and NF (non-fatigued) if no criteria and no exclusionary conditions (n = 196). Relative telomere length (T/S ratio) was measured using DNA from whole blood and real-time PCR. General linear models were used to estimate the association of illness groups or T/S ratio with demographics, biological measures and covariates with significance set at p < 0.05. The mean T/S ratio differed significantly by illness group (p = 0.0017); the T/S ratios in CFS (0.90 ± 0.03) and ISF (0.94 ± 0.02) were each significantly lower than in NF (1.06 ± 0.04). Differences in T/S ratio by illness groups remained significant after adjustment for covariates of age, sex, body mass index, waist-hip ratio, post-exertional malaise and education attainment. Telomere length was shorter by 635, 254 and 424 base pairs in CFS, CFS-X and ISF, respectively, compared to NF. This shorter telomere length translates to roughly 10.1-20.5, 4.0-8.2 and 6.6-13.7 years of additional aging in CFS, CFS-X and ISF compared to NF respectively. Further, stratified analyses based on age and sex demonstrated that the association of ME/CFS with short telomeres is largely moderated by female subjects < 45 years old. This study found a significant association of ME/CFS with premature telomere attrition that is largely moderated by female subjects < 45 years old. Our results indicate that ME/CFS could be included in the list of conditions associated with accelerated aging. Further work is needed to evaluate the functional significance of accelerated aging in ME/CFS.


Improving professional judgments of risk and amenability in juvenile justice.
The dual requirement to ensure community safety and promote a youthful offender's positive development permeates policy and frames daily practice in juvenile justice. Balancing those two demands, explain Edward Mulvey and Anne-Marie Iselin, requires justice system professionals at all levels to make extremely difficult decisions about the likely risk and amenability to treatment of adolescent offenders. Mulvey and Iselin point out that although various forms of "structured" decision-making instruments are used widely in other fields, juvenile justice professionals today make limited use of these tools. Instead, they make decisions based mainly on their intuition about whether the adolescent before them is more likely to harm the community or to use justice system services to turn his life around. The reluctance of busy court professionals to use these structured decision-making tools, they say, arises partly from their heavy work load. But it also grows out of the ethos of the juvenile court itself. Restricting an adolescent's freedom or access to interventions based on a tallying of empirical data is antithetical to viewing each adolescent as a unique individual whose life chances may remain intact with developmentally appropriate intervention. Mulvey and Iselin recommend and examine three ways to integrate structured judgment approaches into the juvenile justice system that both capitalize on their strengths and support the court's attempts to provide fair, individualized justice. First, more reliance on actuarial methods at detention and intake would promote more efficient and equitable screening of cases for subsequent court involvement. Second, the use of structured decision making by probation officers could provide more consistent and valid guidance for the court when formulating dispositions. Finally, implementing structured data systems to chart the progress of adolescents in placement could allow judges to oversee service providers more effectively. The challenge for the juvenile system, say the authors, will be to harness the new capacities of the science of decision making and of computer technology to increase the efficiency of its limited resources for the benefit both of the community and of the adolescents in the system.


Organizational factors that influence information technology diffusion in academic health sciences centers.
To identify the organizational factors which influence the diffusion of end user online literature searching, the computer-based patient record, and electronic mail systems in academic health sciences centers in the United States. A total of 1335 individuals working in informatics and library areas at 67 academic health sciences centers in the U.S. were surveyed. Multivariate techniques were used to evaluate the relationship between the set of six organizational factors and two measures of innovation diffusion. A Guttman-like scale was developed to measure infusion, or depth or sophistication, of each of the three innovations at each institution. Diffusion was measured by a question previously developed for another study. Six independent variables were measured via five formerly developed scales and one new one. The overall response rate was 41%. The set of organizational variables produced significant results in the diffusion of each of the three innovations, with individual variables influencing diffusion to varying degrees. The same set produced significant results in relation to infusion only for online searching. There was little or no correlation between infusion and diffusion for each innovation. Organizational attributes are important predictors for diffusion of information technology innovations. Individual variables differ in their effect on each innovation. The set of attributes seems less able to predict infusion. It is recommended that both infusion and diffusion be measured in future studies because there is little relation between them. It is further recommended that individuals charged with implementing information technology in the health sciences receive training in managing organizational issues.