Characteristics of high-echoic objects in the hepatic vessels of patients with cardiopulmonary arrest: a prospective cohort study.
High-echoic objects in the hepatic vessels of patients with cardiopulmonary arrest (CPA) are frequently detected by ultrasonography. To demonstrate this phenomenon and clarify its clinical characteristics. In a tertiary care academic medical centre, 203 CPA patients were evaluated by ultrasonography. CT determined the origin and location of high-echoic objects detected in the liver. The frequency and characteristics of this phenomenon were investigated. The background, laboratory data and survival rate were compared between patients with and without high-echoic objects. High-echoic objects were seen in 73 (36.0%) patients and could clearly be detected in the hepatic veins of 41 (56.2%) patients. CT confirmed that these were gas in 27 of 53 patients, and were clearly visible in the hepatic veins in 12 (44.4%) patients. Hepatic portal venous gas was not identified. Compared to patients without high-echoic objects, witnessed arrest (p<0.001), bystander cardiopulmonary resuscitation (p=0.005), ventricular fibrillation or pulseless electrical activity (p=0.012) and return of spontaneous circulation (p=0.018) were significantly less frequent in patients with high-echoic objects. These patients had a lower incidence of survival to discharge (1.4% vs 7.7%, p=0.100). Multivariate analysis showed that absence of high-echoic objects was a marginally significant factor in association with return of spontaneous circulation (p=0.052). High-echoic objects were often observed on ultrasonography in CPA patients; these objects were considered hepatic venous gas. The presence of high-echoic objects may be a poor prognostic sign in patients with CPA.


Thermodynamic characterization of allosteric glycogen phosphorylase inhibitors.
Glycogen phosphorylase (GP) is a validated target for the treatment of type 2 diabetes. Here we describe highly potent GP inhibitors, AVE5688, AVE2865, and AVE9423. The first two compounds are optimized members of the acyl urea series. The latter represents a novel quinolone class of GP inhibitors, which is introduced in this study. In the enzyme assay, both inhibitor types compete with the physiological activator AMP and act synergistically with glucose. Isothermal titration calorimetry (ITC) shows that the compounds strongly bind to nonphosphorylated, inactive GP (GPb). Binding to phosphorylated, active GP (GPa) is substantially weaker, and the thermodynamic profile reflects a coupled transition to the inactive (tense) conformation. Crystal structures confirm that the three inhibitors bind to the AMP site of tense state GP. These data provide the first direct evidence that acyl urea and quinolone compounds are allosteric inhibitors that selectively bind to and stabilize the inactive conformation of the enzyme. Furthermore, ITC reveals markedly different thermodynamic contributions to inhibitor potency that can be related to the binding modes observed in the cocrystal structures. For AVE5688, which occupies only the lower part of the bifurcated AMP site, binding to GPb (Kd = 170 nM) is exclusively enthalpic (Delta H = -9.0 kcal/mol, TDelta S = 0.3 kcal/mol). The inhibitors AVE2865 (Kd = 9 nM, Delta H = -6.8 kcal/mol, TDelta S = 4.2 kcal/mol) and AVE9423 (Kd = 24 nM, Delta H = -5.9 kcal/mol, TDelta S = 4.6 kcal/mol) fully exploit the volume of the binding pocket. Their pronounced binding entropy can be attributed to the extensive displacement of solvent molecules as well as to ionic interactions with the phosphate recognition site.


Studies of ionic current rectification using polyethyleneimines coated glass nanopipettes.
The modification of glass nanopipettes with polyethyleneimines (PEIs) has been successfully achieved by a relatively simple method, and the smallest tip opening is around 3 nm. Thus, in a much wider range of glass pipettes with radii from several nanometers to a few micrometers, the ion current rectification (ICR) phenomenon has been observed. The influences of different KCl concentrations, pH values, and tip radii on the ICR are investigated in detail. The sizes of PEIs have been determined by dynamic light scattering, and the effect of the sizes of PEIs for the modification, especially for a few nanometer-pipettes in radii, is also discussed. These findings systemically confirm and complement the theoretical model and provide a platform for possible selectively molecular detection and mimic biological ion channels.


Locked nucleic acid (LNA) enhances binding affinity of triazole-linked DNA towards RNA.
Oligonucleotides containing internal triazole-3'-LNA linkages bind to complementary RNA with similar affinity and specificity to unmodified oligonucleotides, and significantly better than oligonucleotides containing triazole alone. In contrast LNA on the 5'-side of the triazole does not stabilise duplexes. Triazole-LNA confers great resistance towards enzymatic degradation relative to LNA alone.


Point mutations in the beta-subunit of cytochrome b558 leading to X-linked chronic granulomatous disease.
The NADPH:O2 oxidoreductase of phagocytic leukocytes is an important enzyme for the bactericidal activity of these cells. Cytochrome b558 is a membrane component of this enzyme. In X-linked chronic granulomatous disease (Xb- CGD) the phagocytes are defective in the beta-subunit (gp91-phox) of this cytochrome. We have studied the genetic defect in a group of six X-linked CGD patients characterized by complete or partial loss of cytochrome b558 with the use of the polymerase chain reaction. All patients had a different single point mutation in the gp91-phox gene, indicating that the genetic defect in Xb- CGD is very heterogeneous. In one patient the mutation leads to a premature termination codon. In the other five cases these mutations predict incorporation of a different amino acid. The mutations were with one exception found in the N-terminal half of the protein, suggesting that this part of cytochrome b558 is important for the binding of the heme or for formation of a stable complex with p22-phox. Two histidyl residues were found that might be ligands of the heme iron.


Leukocyte common antigen-related phosphatase is a functional receptor for chondroitin sulfate proteoglycan axon growth inhibitors.
Chondroitin sulfate proteoglycans (CSPGs) are a family of extracellular matrix molecules with various functions in regulating tissue morphogenesis, cell division, and axon guidance. A number of CSPGs are highly upregulated by reactive glial scar tissues after injuries and form a strong barrier for axonal regeneration in the adult vertebrate CNS. Although CSPGs may negatively regulate axonal growth via binding and altering activity of other growth-regulating factors, the molecular mechanisms by which CSPGs restrict axonal elongation are not well understood. Here, we identified a novel receptor mechanism whereby CSPGs inhibit axonal growth via interactions with neuronal transmembrane leukocyte common antigen-related phosphatase (LAR). CSPGs bind LAR with high affinity in transfected COS-7 cells and coimmunoprecipitate with LAR expressed in various tissues including the brain and spinal cord. CSPG stimulation enhances activity of LAR phosphatase in vitro. Deletion of LAR in knock-out mice or blockade of LAR with sequence-selective peptides significantly overcomes neurite growth restrictions of CSPGs in neuronal cultures. Intracellularly, CSPG-LAR interaction mediates axonal growth inhibition of neurons partially via inactivating Akt and activating RhoA signals. Systemic treatments with LAR-targeting peptides in mice with thoracic spinal cord transection injuries induce significant axon growth of descending serotonergic fibers in the vicinity of the lesion and beyond in the caudal spinal cord and promote locomotor functional recovery. Identification of LAR as a novel CSPG functional receptor provides a therapeutic basis for enhancing axonal regeneration and functional recovery after CNS injuries in adult mammals.


uPAR targeted radionuclide therapy with (177)Lu-DOTA-AE105 inhibits dissemination of metastatic prostate cancer.
The urokinase-type plasminogen activator receptor (uPAR) is implicated in cancer invasion and metastatic development in prostate cancer and provides therefore an attractive molecular target for both imaging and therapy. In this study, we provide the first in vivo data on an antimetastatic effect of uPAR radionuclide targeted therapy in such lesions and show the potential of uPAR positron emission tomography (PET) imaging for identifying small foci of metastatic cells in a mouse model of disseminating human prostate cancer. Two radiolabeled ligands were generated in high purity and specific activity: a uPAR-targeting probe ((177)Lu-DOTA-AE105) and a nonbinding control ((177)Lu-DOTA-AE105mut). Both uPAR flow cytometry and ELISA confirmed high expression levels of the target uPAR in PC-3M-LUC2.luc cells, and cell binding studies using (177)Lu-DOTA-AE105 resulted in a specific binding with an IC50 value of 100 nM in a competitive binding experiment. In vivo, uPAR targeted radionuclide therapy significantly reduced the number of metastatic lesions in the disseminated metastatic prostate cancer model, when compared to vehicle and nontargeted (177)Lu groups (p < 0.05) using bioluminescence imaging. Moreover, we found a significantly longer metastatic-free survival, with 65% of all mice without any disseminated metastatic lesions present at 65 days after first treatment dose (p = 0.047). In contrast, only 30% of all mice in the combined control groups treated with (177)Lu-DOTA-AE105mut or vehicle were without metastatic lesions. No treatment-induced toxicity was observed during the study as evaluated by observing animal weight and H&E staining of kidney tissue (dose-limiting organ). Finally, uPAR PET imaging using (64)Cu-DOTA-AE105 detected all small, disseminated metastatic foci when compared with bioluminescence imaging in a cohort of animals during the treatment study. In conclusion, uPAR targeted radiotherapy resulted in a significant reduction in the number of metastatic lesions in a human metastatic prostate cancer model. Furthermore, we have provided the first evidence of the potential for identification of small metastatic lesions using uPAR PET imaging in disseminated prostate cancer, illustrating the promising strategy of uPAR theranostics in prostate cancer.


Conservation of a functional hierarchy between mammalian and insect Hox/HOM genes.
We have generated several transgenic Drosophila strains containing different mouse Hox genes under heat shock control and studied how their generalized expression affects Drosophila larval patterns. We find that they have spatially restricted effects which correlate with their genetic order and expression pattern in the mouse; as they are expressed more posteriorly in the mouse, they have more extensive effects in Drosophila. The generalized expressions of Hoxd-8 and d-9 modify Drosophila anterior head segment(s), but have no effect in the rest of the body. Hoxd-10 expression affects head and thorax, but not the abdomen. Finally, Hoxd-11 alters head, thorax not the abdomen. Finally, Hoxd-11 alters head, thorax and abdomen. The developmental effect of the Hox genes consists of a homeotic transformation of the affected segment(s), which exhibit a 'ground' pattern similar to that obtained in the absence of homeotic information, suggesting that Hox genes are able to inactivate Drosophila homeotic genes, but do not specify a pattern of their own. A partial exception is Hoxd-11 which, even though it has a general suppressing effect, can also activate the resident Abdominal-B and empty spiracles genes in ectopic positions. Our results strongly suggest a general conservation of the functional hierarchy of homeotic genes that correlates with genetic order and expression patterns.


An osmotically tolerant inner medullary collecting duct cell line from an SV40 transgenic mouse.
The terminal inner medullary collecting duct (IMCD) plays an important role in determining the final urinary composition. Currently, there is no continuous cell line derived from this nephron segment. We have developed a cell line derived from the terminal IMCD of mice transgenic for the early region of simian virus SV40 (large T antigen). This cell line, mIMCD-3, retains many differentiated characteristics of this nephron segment including high transepithelial resistance (1,368 +/- 172 omega.cm2), inhibition of apical-to-basal sodium flux by amiloride (41 +/- 7%) and by atrial natriuretic peptide (ANP) (40 +/- 9%), the presence of the amiloride-sensitive sodium channel as determined by Western blot analysis, and accumulation of the major organic osmolytes in response to hypertonic stress. Significantly, mIMCD-3 cells adapted readily and were able to grow in hypertonic medium supplemented with NaCl and urea up to 910 mosmol/kgH2O. These extreme osmotic conditions exist in the renal medulla in vivo but are known to be lethal to most other cells. This cell line should be highly useful for the study of the cellular adaptation to osmotic stress and the cell biology and transport physiology of this nephron segment.


The impact of electrical injuries on long-term outcomes: A Burn Model System National Database study.
Electrical injuries exhibit significant acute and long-term sequelae. Amputation and neurological deficits are common in electrical injury survivors. There is a paucity of information on the long-term outcomes of this population. Therefore, this study examines the long-term outcomes of electrical injuries by comparing them to fire/flame injuries. Data from the Burn Model System National Database collected between 1996 and 2015 was examined. Demographic and clinical characteristics for adult burn survivors with electrical and fire/flame injuries were compared. Satisfaction With Life Scale (SWLS), Short Form-12 Physical Composite Score (SF-12 PCS), Short Form-12 Mental Composite Score (SF-12 MCS), and employment status were examined at 24 months post-injury. Linear and logistic regression models were used to assess differences in outcome measures between groups, controlling for demographic and clinical variables. A total of 1147 adult burn survivors (111 with electrical injuries; 1036 with fire/flame injuries) were included in this study. Persons with electrical injuries were more likely to be male and injured at work (p<0.001). SF-12 PCS scores were significantly worse for survivors with electrical injuries at 24 months post-injury than survivors with fire/flame injuries (p<0.01). Those with electrical injuries were nearly half as likely to be employed at 24 months post-injury than those with fire/flame injuries (p=0.002). There were no significant differences in SWLS and SF-12 MCS between groups. Adult survivors with electrical injuries reported worse physical health and were less likely to be employed at 24 months post-injury compared to survivors with fire/flame injuries. A more detailed understanding of return to work barriers and work accommodations is merited for the electrical injury population. Furthermore, the results of this study should inform future resource allocation for the physical health and employment needs of this population.


A three-year national follow-up study on the development of community-level cancer rehabilitation in Denmark.
Aims: Scandinavian cancer care policies emphasise community-level rehabilitation services, but little is known about changes in service provision over time. This follow-up study explores development in these services in Danish municipalities, focusing on availability, utilisation and organisation of services, including existing opportunities and challenges. Methods: A national survey among all 98 Danish municipalities was conducted in 2013 (baseline) and repeated in 2016 (follow-up). The electronic questionnaire comprised closed- and open-ended questions. Data were analysed using descriptive statistics and content analysis. Results: A total of 93 municipalities responded (95% response rate) and the services offered primarily comprised group physical activity, dietary advice, smoking cessation and individual counselling on physical activity. The number of patients enrolled was below the estimated number needing rehabilitation in Denmark. Inequality in utilisation by ethnicity, age and gender was reported. Key challenges for the delivery of services were: inadequate referral and recruitment procedures; lack of needs assessment tools; obstacles to ensuring collaboration and referral of patients between hospitals and municipalities; and inadequate evidence on the rehabilitation's effect. Key recommendations include ensuring collaboration between municipalities; provision of diagnosis-specific group-based activities; services focusing on physical activity; and gender-specific activities directed particularly at men. Conclusions: This study, which highlights improvements in the provision of community-level cancer rehabilitation, recommends that more effort be made to ensure equality in utilisation across patient groups, improved integration of municipal-level services into cancer care trajectories, more uniform documentation of service delivery and the enforcement of patient outcomes to gradually build a more robust evidence base for community-level cancer rehabilitation.


Reaching the 'first 90': Gaps in coverage of HIV testing among people living with HIV in 16 African countries.
UNAIDS has recently proposed a set of three ambitious targets that, if achieved, are predicted to end the AIDS epidemic by 2030. The targets, known as 90-90-90, call for 90% of people living with HIV (PLHIV) to know their status, 90% of PLHIV to receive antiretroviral therapy, and 90% of those on antiretroviral therapy to achieve viral suppression by the year 2020. We examine the first of these targets, focusing on sub-Saharan Africa, the region of the world most affected by HIV, to measure the proportion of PLHIV estimated to know their HIV status, and to identify background and behavioral characteristics significantly associated with gaps in ever testing among PLHIV. We analyze cross-sectional population-based data from the Demographic and Health Surveys (DHS) and AIDS Indicator Surveys (AIS) fielded since 2010 in 16 sub-Saharan African countries where voluntary serological testing was recently conducted: Burkina Faso, Cameroon, Chad, Cote d'Ivoire, Ethiopia, Gabon, Lesotho, Malawi, Namibia, Rwanda, Sierra Leone, Tanzania, Togo, Uganda, Zambia, and Zimbabwe. Survey response rates averaged 95.0% (range 89.3-99.5%), while consent to serotesting averaged 94.9% (range 88.7-99.6%). This study, which includes more than 14,000 respondents living with HIV, finds that 69% of PLHIV in the average study country have ever been tested for HIV (range 34-95%). Based on timing of the last test and on ART coverage, we estimate that 54% of PLHIV in the average country are aware of their status (range 26-84%). Adjusted logistic regression finds that men (median adjusted odds ratio [AOR] = 0.38), adults with less than primary education (median AOR = 0.31), and adolescents (median AOR = 0.32) are consistently less likely to have ever been tested for HIV than women, adults with secondary and above education, and adults age 30-39, respectively. In most countries unadjusted logistic regression also finds significant gaps in testing among the poorest groups and those reporting never having had sex. The fact that an average of 54% of PLHIV in these 16 countries are estimated to know their status reflects encouraging progress. However, not only is this average far short of the 90% target set by UNAIDS for 2020, but it also implies that in the average study country nearly one-half of PLHIV are unable to access lifesaving care and treatment because they are unaware that they are HIV-positive. Several gaps in HIV testing coverage exist, particularly among adolescents, the least educated, and men. While the need to target demographic groups at greatest risk of HIV continues, additional interventions focused on reaching men and on reaching socially vulnerable populations such as adolescents, the poorest, and the least educated are essential.


Does a viral infection cause complex regional pain syndrome?
In 1990 Omura, Y. reported that Herpes Simplex Virus Type 1 as the major cause of chronic intractable pain and its effective treatment using mixture of EPA & DHA with Selective Drug Uptake Enhancement Method. Subsequently among the other causes of pain, he included Chlamydia Trachomatis, Borrelia Burgdorferi, Mycobacterium Tuberculosis, human Herpes Virus type 6, and Circulatory Disturbances. In order to test possible involvement of viral infection in Complex Regional Pain Syndrome (CRPS), a disease which usually occurs in the extremities, we did a study of 17 patients with CRPS. They were examined for Herpes Simplex Virus (HSV) and Varicella Zoster Virus (VZV) by measuring IgG and IgM antibody titers, and 14 of these patients were also examined for Cytomegalo-Virus (CMV). As a control group 100 healthy Japanese employees at SRL, Inc. were also studied. In CRPS group, HSV IgG was positive in 12 of the 17 patients with an average antibody titer of 90.0 EIA value. VZV IgG was positive in all 17 patients with an average antibody titer of 26.8 EIA value. CMV IgG was positive in all 14 patients with an average antibody titer of 66.6 UA/ml. In control group, HSV IgG was positive in 54 subjects with an average antibody titer of 42.3 EIA value. VZV IgG was positive in 97 subjects with an average antibody titer of 26.2 EIA value. CMV IgG was positive in 82 subjects. There were no significant differences of positive rate of IgG antibody for the three viruses between patient and control groups. Although the difference was not significant, the average antibody titers of HSV in CRPS group were more than twice of those in healthy group. Antibody titers were almost equal in both groups for VZV. Possibly, some people in the control group who had latent virus, were also asymptomatic. In 2000, Takasaki, I. et al. in a separate animal study, inoculated with HSV Type-I the shin of the mouse causing allodynia and hyperalgesia (which are some of the characteristic findings seen in CRPS in humans). Also, VZV, which causes shingles which is sometimes followed by Post-Herpetic Neuralgia (PHN), is in the same family of HSV. As PHN resembles CRPS in symptoms, it is possible that HSV contributes to CRPS. Therefore, virus infection theory is an attractive hypothesis that accounts for many enigmas of CRPS.


Fanm ayisyen pap kase: respecting the right to health of Haitian women and girls.
Only in recent years has violence against women begun to receive international attention as both a public health and human rights concern. This article argues that the right to be free from sexual violence is a fundamental component of the right to health, and the need is particularly acute in post-disaster contexts. This article uses post-earthquake Haiti as a case study to illustrate conditions for women and girls who suffer daily threats of physical, emotional, economic, and social harm in ways that have no direct parallels for their male counterparts. In addition, this article discusses the reasons that the humanitarian response in Haiti has not effectively protected women and girls and has instead exacerbated structural inequalities, making women, girls, and their families even more vulnerable to human rights violations including interference in their right to health. The article argues that the failure to guarantee the right of women to be free from sexual violence - an essential component of the right to health - is due in large part to the exclusion of displaced women from meaningful participation in formal humanitarian interventions.


Factors that modify the association between knee pain and mobility limitation in older women: the Women's Health and Aging Study.
To investigate the influence of pain severity, knee extensor muscle weakness, obesity, depression, and activity on the association between recent knee pain and limitation of usual and fast paced walking, and ability to rise from a chair. A cross sectional analysis of 769 older women (mean age 77.8, range 65-101) with physical disability, but no severe cognitive impairment. Severity of knee pain in the past month was classified as none, moderate, or severe. Mobility was measured using timed performance tests. The prevalence of recent knee pain was 53% (408/769). One third of the women with pain reported it to be severe. In general, knee pain was only significantly associated with limited mobility if severe. Obesity, activity and, to a lesser extent, depression intensified the effects of pain. Knee extensor weakness did not. Obesity was a distinctive risk factor in that it substantially increased the risk of mobility limitation, but only in women with pain. In women who had severe pain, activity (walking more than three city blocks in the past week) increased the risk of walking disability more than inactivity. Depression had a minor, but statistically significant effect on walking ability, but not the ability to rise from a chair. In older women with recent knee pain, a high pain severity score, obesity, and activity are important factors that increase the risk of mobility limitation.


CORRECTING FOR MEASUREMENT ERROR IN LATENT VARIABLES USED AS PREDICTORS.
This paper represents a methodological-substantive synergy. A new model, the Mixed Effects Structural Equations (MESE) model which combines structural equations modeling and item response theory is introduced to attend to measurement error bias when using several latent variables as predictors in generalized linear models. The paper investigates racial and gender disparities in STEM retention in higher education. Using the MESE model with 1997 National Longitudinal Survey of Youth data, I find prior mathematics proficiency and personality have been previously underestimated in the STEM retention literature. Pre-college mathematics proficiency and personality explain large portions of the racial and gender gaps. The findings have implications for those who design interventions aimed at increasing the rates of STEM persistence among women and under-represented minorities.


Comparison of individual, group and environmental sampling strategies to conduct influenza surveillance in pigs.
Influenza A virus (IAV) is an important pathogen in pigs that affects productivity and has important public health implications because of its zoonotic nature. Surveillance is central to the control of influenza, however, detection of IAV infections can be challenging in endemically infected herds with low prevalence of infection. In groups of suckling (18-21 days of age) and growing (35-45 days of age) pigs, we compared various sampling approaches to detect, isolate and sequence IAV using individual (nasal swabs, nasal wipes and oropharyngeal swabs), group (oral fluids, surface wipes and sow udder skin wipes) and environmental (airborne particles deposited on surfaces and air samples) sampling approaches. All samples were tested by IAV rRT-PCR and a subset was used for virus isolation and direct sequencing. In general, environmental and group samples resulted in higher odd ratios (range = 3.87-16.5, p-value < 0.05) of detecting a positive sample by rRT-PCR compared to individual pooled samples, except for oropharyngeal swabs (OR = 8.07, p-value < 0.05). In contrast, individual samples were most likely to yield a viral isolate by cell culture. Oropharyngeal swabs in suckling pigs (78.4%), and nasal swabs (47.6%) or nasal wipes (45%) in growing pigs, and udder wipes in lactating sows (75%) were the preferred samples to obtain an isolate. Our findings indicate that group and environmental sampling strategies should be considered in influenza surveillance programs in particular if the goal is just to detect infection. This study provides new information on sampling approaches to conduct effective influenza surveillance in pigs and identifies udder wipes from lactating sows as a novel sample type that offers a convenient, cheap and sensitive manner to monitor IAV in litters prior to weaning.


Working memory, reading, and mathematical skills in children with developmental coordination disorder.
The aim of the present study was investigate the relationship between working memory and reading and mathematical skills in 55 children diagnosed with developmental coordination disorder (DCD). The findings indicate a pervasive memory deficit in all memory measures. In particular, deficits observed in visuospatial short-term and working memory tasks were significantly worse than in the verbal short-term memory ones. On the basis of these deficits, the sample was divided into high and low visuospatial memory ability groups. The low visuospatial memory group performed significantly worse on the attainment measures compared to the high visuospatial memory group, even when the contribution of IQ was taken into account. When the sample was divided into high and low verbal working memory ability groups, verbal working memory skills made a unique contribution to attainment only when verbal IQ was taken into account, but not when performance IQ was statistically controlled. It is possible that the processing demands of the working memory tasks together with the active motor component reflected in the visuospatial memory tasks and performance IQ subtest both play a crucial role in learning in children with DCD.


Recognition and management of hereditary hemochromatosis.
Hereditary hemochromatosis is the most common inherited single-gene disorder in people of northern European descent. It is characterized by increased intestinal absorption of iron, with deposition of the iron in multiple organs. Previously, the classic description was combined diabetes mellitus, cutaneous hyperpigmentation and cirrhosis. Increasingly, however, hereditary hemochromatosis is being diagnosed at an earlier, less symptomatic stage. The diagnosis is based on a combination of clinical, laboratory and pathologic findings, including elevated serum transferrin saturation. Life expectancy is usually normal if phlebotomy is initiated before the development of cirrhosis or diabetes mellitus. Hereditary hemochromatosis is associated with mutations in the HFE gene. Between 60 and 93 percent of patients with the disorder are homozygous for a mutation designated C282Y. The HFE gene test is useful in confirming the diagnosis of hereditary hemochromatosis, screening adult family members of patients with HFE mutations and resolving ambiguities concerning iron overload.


Eponyms in cardiopulmonary reflexes.
Heart rate, blood pressure, and vascular tone, as well as ventilator drive, respiratory rate, and breathing pattern, are, at least in part, under the control of specific reflexes. These reflexes are mediated by a complex network of baroreceptors and chemoreceptors in the arterial system of the carotids, aorta, and left heart, including receptors in the left atrium, the ventricle, and the coronary arteries; irritants in the upper airways and stretch receptors in the lower airways; juxtacapillary-located nonmyelinated fibers in the alveoli and in the bronchial arterial system; and muscle spindles that evoke changes in the membrane potential upon alteration of sarcolemmal tension. Some of these reflexes, usually named after the first individual to describe them, have spread as eponyms into propaedeutic education and clinical work. Because these euphonic eponyms are enigmatic to most clinicians today, this article is intended to provide a short overview of these reflexes, including the historical context of their describers. As evidenced by their clinical implications, the eponyms discussed are revealed to be more than curiosities taught during undergraduate medical education.


Homosexual orientation in males: evolutionary and ethological aspects.
Evolutionary theory proposes that adaptive traits are reproduced more successfully than maladaptive traits. Accordingly, natural selection should favor heterosexuality as it facilitates reproduction and the propagation of genes. However, the question becomes, what has maintained homosexuality in a small but consistent percentage of the human population? Research into the evolutionary and hormonal factors associated with a homosexual orientation have yielded provocative but inconsistent results. It also suggests that human sexual orientation, and in particular homosexual orientation, is too complex to be described by one simple model or a single research discipline. The current paper treads a new path and emphasizes an integrative approach for the understanding of homosexuality. The authors examine the combined effects of evolutionary factors and neurohormonal processes on the development of a homosexual orientation. It is suggested that research into the topic could benefit from an examination of and change in some of the assumptions upon which much past research has been based.


Feasibility of Pediatric Game-Based Neurorehabilitation Using Telehealth Technologies: A Case Report.
This case report is the first in a series of reports designed to determine the feasibility of implementing game-based neurorehabilitation using telehealth technologies (GbN+TT) for children with cerebral palsy, evaluate the responsiveness of relevant outcome measures to changes in motor impairment and activity participation after intervention, and identify technological challenges associated with implementation of GbN+TT. The participant completed more than 56 hr of game-based neurorehabilitation over 8 wk using the Timocco platform in his home. The primary measures of motor impairment (Bruininks-Oseretsky Test of Motor Proficiency, Second Edition) and function (Pediatric Motor Activity Log) were both sensitive to change. Results indicate that it is feasible to administer GbN+TT to a child with cerebral palsy and monitor outcomes using standardized assessments.


Understanding the onset of hot streaks across artistic, cultural, and scientific careers.
Across a range of creative domains, individual careers are characterized by hot streaks, which are bursts of high-impact works clustered together in close succession. Yet it remains unclear if there are any regularities underlying the beginning of hot streaks. Here, we analyze career histories of artists, film directors, and scientists, and develop deep learning and network science methods to build high-dimensional representations of their creative outputs. We find that across all three domains, individuals tend to explore diverse styles or topics before their hot streak, but become notably more focused after the hot streak begins. Crucially, hot streaks appear to be associated with neither exploration nor exploitation behavior in isolation, but a particular sequence of exploration followed by exploitation, where the transition from exploration to exploitation closely traces the onset of a hot streak. Overall, these results may have implications for identifying and nurturing talents across a wide range of creative domains.


Ligand-gating by Ca2+ is rate limiting for physiological operation of BK(Ca) channels.
Large conductance Ca(2+)- and voltage-activated potassium channels (BKCa) shape neuronal excitability and signal transduction. This reflects the integrated influences of transmembrane voltage and intracellular calcium concentration ([Ca(2+)]i) that gate the channels. This dual gating has been mainly studied as voltage-triggered gating modulated by defined steady-state [Ca(2+)]i, a paradigm that does not approximate native conditions. Here we use submillisecond changes of [Ca(2+)]i to investigate the time course of the Ca(2+)-triggered gating of BKCa channels expressed in Chinese hamster ovary cells at distinct membrane potentials in the physiological range. The results show that Ca(2+) can effectively gate BKCa channels and that Ca(2+) gating is largely different from voltage-driven gating. Most prominently, Ca(2+) gating displays a pronounced delay in the millisecond range between Ca(2+) application and channel opening (pre-onset delay) and exhibits slower kinetics across the entire [Ca(2+)]i-voltage plane. Both characteristics are selectively altered by co-assembled BKβ4 or an epilepsy-causing mutation that either slows deactivation or speeds activation and reduces the pre-onset delay, respectively. Similarly, co-assembly of the BKCa channels with voltage-activated Ca(2+) (Cav) channels, mirroring the native configuration, decreased the pre-onset delay to submillisecond values. In BKCa-Cav complexes, the time course of the hyperpolarizing K(+)-current response is dictated by the Ca(2+) gating of the BKCa channels. Consistent with Cav-mediated Ca(2+) influx, gating was fastest at hyperpolarized potentials, but decreased with depolarization of the membrane potential. Our results demonstrate that under experimental paradigms meant to approximate the physiological conditions BKCa channels primarily operate as ligand-activated channels gated by intracellular Ca(2+) and that Ca(2+) gating is tuned for fast responses in neuronal BKCa-Cav complexes.


Typologies of male batterers: three subtypes and the differences among them.
Previous typologies of male batterers, including typologies developed by means of rational-deductive and empirical-inductive strategies, are reviewed. On the basis of this review, 3 descriptive dimensions (i.e., severity of marital violence, generality of the violence [toward the wife or toward others], and psychopathology/personality disorders) that consistently have been found to distinguish among subtypes of batterers are identified. These dimensions are used to propose a typology consisting of 3 subtypes of batterers (i.e., family only, dysphoric/borderline, and generally violent/antisocial). A developmental model of marital violence is then presented, and the previous literature is reviewed to examine how each batterer subtype might differ on variables of theoretical interest. Finally, some of the methodological limitations of previous typology research are reviewed, and suggestions for future work are offered.


The relative influence of geographic location and reach-scale habitat on benthic invertebrate assemblages in six ecoregions.
The objective of this study was to determine the relative influence of reach-specific habitat variables and geographic location on benthic invertebrate assemblages within six ecoregions across the Western USA. This study included 417 sites from six ecoregions. A total of 301 taxa were collected with the highest richness associated with ecoregions dominated by streams with coarse substrate (19-29 taxa per site). Lowest richness (seven to eight taxa per site) was associated with ecoregions dominated by fine-grain substrate. Principle component analysis (PCA) on reach-scale habitat separated the six ecoregions into those in high-gradient mountainous areas (Coast Range, Cascades, and Southern Rockies) and those in lower-gradient ecoregions (Central Great Plains and Central California Valley). Nonmetric multidimensional scaling (NMS) models performed best in ecoregions dominated by coarse-grain substrate and high taxa richness, along with coarse-grain substrates sites combined from multiple ecoregions regardless of location. In contrast, ecoregions or site combinations dominated by fine-grain substrate had poor model performance (high stress). Four NMS models showed that geographic location (i.e. latitude and longitude) was important for: (1) all ecoregions combined, (2) all sites dominated by coarse-grain sub strate combined, (3) Cascades Ecoregion, and (4) Columbia Ecoregion. Local factors (i.e. substrate or water temperature) seem to be overriding factors controlling invertebrate composition across the West, regardless of geographic location.


Implant-derived magnesium induces local neuronal production of CGRP to improve bone-fracture healing in rats.
Orthopedic implants containing biodegradable magnesium have been used for fracture repair with considerable efficacy; however, the underlying mechanisms by which these implants improve fracture healing remain elusive. Here we show the formation of abundant new bone at peripheral cortical sites after intramedullary implantation of a pin containing ultrapure magnesium into the intact distal femur in rats. This response was accompanied by substantial increases of neuronal calcitonin gene-related polypeptide-α (CGRP) in both the peripheral cortex of the femur and the ipsilateral dorsal root ganglia (DRG). Surgical removal of the periosteum, capsaicin denervation of sensory nerves or knockdown in vivo of the CGRP-receptor-encoding genes Calcrl or Ramp1 substantially reversed the magnesium-induced osteogenesis that we observed in this model. Overexpression of these genes, however, enhanced magnesium-induced osteogenesis. We further found that an elevation of extracellular magnesium induces magnesium transporter 1 (MAGT1)-dependent and transient receptor potential cation channel, subfamily M, member 7 (TRPM7)-dependent magnesium entry, as well as an increase in intracellular adenosine triphosphate (ATP) and the accumulation of terminal synaptic vesicles in isolated rat DRG neurons. In isolated rat periosteum-derived stem cells, CGRP induces CALCRL- and RAMP1-dependent activation of cAMP-responsive element binding protein 1 (CREB1) and SP7 (also known as osterix), and thus enhances osteogenic differentiation of these stem cells. Furthermore, we have developed an innovative, magnesium-containing intramedullary nail that facilitates femur fracture repair in rats with ovariectomy-induced osteoporosis. Taken together, these findings reveal a previously undefined role of magnesium in promoting CGRP-mediated osteogenic differentiation, which suggests the therapeutic potential of this ion in orthopedics.


Primary prevention and risk factor reduction in coronary heart disease mortality among working aged men and women in eastern Finland over 40 years: population based observational study.
To estimate how much changes in the main risk factors of cardiovascular disease (smoking prevalence, serum cholesterol, and systolic blood pressure) can explain the reduction in coronary heart disease mortality observed among working aged men and women in eastern Finland. Population based observational study. Eastern Finland. 34,525 men and women aged 30-59 years who participated in the national FINRISK studies between 1972 and 2012. Change in main cardiovascular risk factors through population based primary prevention. Predicted and observed age standardised mortality due to coronary heart disease. Predicted change was estimated with a logistic regression model using risk factor data collected in nine consecutive, population based, risk factor surveys conducted every five years since 1972. Data on observed mortality were obtained from the National Causes of Death Register. During the 40 year study period, levels of the three major cardiovascular risk factors decreased except for a small increase in serum cholesterol levels between 2007 and 2012. From years 1969-1972 to 2012, coronary heart disease mortality decreased by 82% (from 643 to 118 deaths per 100,000 people) and 84% (114 to 17) among men and women aged 35-64 years, respectively. During the first 10 years of the study, changes in these three target risk factors contributed to nearly all of the observed mortality reduction. Since the mid-1980s, the observed reduction in mortality has been larger than predicted. In the last 10 years of the study, about two thirds (69% in men and 66% in women) of the reduction could be explained by changes in the three main risk factors, and the remaining third by other factors. Reductions in disease burden and mortality due to coronary heart disease can be achieved through the use of population based primary prevention programmes. Secondary prevention among high risk individuals and treatment of acute events of coronary heart disease could confer additional benefit.


25th ANNIVERSARY OF CLONING BY SOMATIC CELL NUCLEAR TRANSFER: Generation of genetically engineered livestock using somatic cell nuclear transfer.
Genetic engineering (GE) of livestock initially has been accomplished primarily using pronuclear microinjection into zygotes (1985-1996). The applications of the technology were limited due to low integration efficiency, aberrant transgene expression resulting from random integration and the presence of genetic mosaicism in transgenic founder animals. Despite enormous efforts to established embryonic stem cells (ESCs) for domestic species, the ESC GE technology does not exist for livestock. Development of somatic cell nuclear transfer (SCNT) has bypassed the need in livestock ESCs and revolutionized the field of livestock transgenesis by offering the first cell-based platform for precise genetic manipulation in farm animals. For nearly two decades since the birth of Dolly (1996-2013), SCNT was the only method used for the generation of knockout and knockin livestock. Arrival of CRISPRS/Cas9 system, a new generation of gene-editing technology, gave us an ability to introduce precise genome modifications easily and efficiently. This technological advancement accelerated production of GE livestock by SCNT and reinstated zygote micromanipulation as an important GE approach. The primary advantage of the SCNT technology is the ability to confirm in vitro that the desired genetic modification is present in the somatic cells prior to animal production. The edited cells could also be tested for potential off-target mutations. Additionally, this method eliminates the risk of genetic mosaicism frequently observed following zygote micromanipulation. Despite its low efficiency, SCNT is a well-established procedure in numerous laboratories around the world and will continue to play an important role in the GE livestock field.


Resistance of mucoid Pseudomonas aeruginosa to nonopsonic phagocytosis by alveolar macrophages in vitro.
A unique, recently described rat alveolar macrophage cell line (NR8383) was used to study the interaction of the pulmonary immune system with a mucoid cystic fibrosis isolate of Pseudomonas aeruginosa (SRM-3), its nonmucoid revertant (SRM-3R), and a non-cystic fibrosis isolate (PAO-1). Strain SRM-3 was cultivated in a chemostat system to allow maintenance of an entirely mucoid population. The alveolar macrophage response to the mucoid and nonmucoid strains of P. aeruginosa was determined by visually quantitating phagocytosis in acridine orange-stained monolayers and measuring the induction of an oxidative burst as indicated by chemiluminescence and H2O2 production. In all experiments, fewer than 2% of the NR8383 cells engulfed the mucoid SRM-3 isolate, while SRM-3R and PAO-1 were phagocytized by 15 and 41%, respectively. Opsonization by normal serum (complement) provided minimal phagocytic enhancement of these strains, whereas specific anti-P. aeruginosa antibody slightly elevated phagocytic responses to strains with nonmucoid phenotypes while providing a sevenfold increase in uptake of SRM-3. Chemiluminescent and H2O2 responses were comparable with the levels of phagocytosis observed, with very little or no response to the mucoid strain SRM-3. The data indicate that the strains with mucoid phenotypes are refractile to ingestion and that studies which describe ingestion of mucoid strains were likely measuring ingestion of revertants. Alginic acid (2 mg/ml) was found to inhibit stimulation of macrophage response to the opsonized and unopsonized nonmucoid strain PAO-1.


Offshore wind farms as productive sites or ecological traps for gadoid fishes?--impact on growth, condition index and diet composition.
With the construction of wind farms all across the North Sea, numerous artificial reefs are created. These windmill artificial reefs (WARs) harbour high abundances of fish species which can be attracted from elsewhere or can be the result of extra production induced by these wind farms. To resolve the attraction-production debate in suddenly altered ecosystems (cf. wind farms), the possible consequences of attraction should be assessed; thereby bearing in mind that ecological traps may arise. In this paper we investigated whether the wind farms in the Belgian part of the North Sea act as ecological traps for pouting and Atlantic cod. Length-at-age, condition and diet composition of fish present at the windmill artificial reefs was compared to local and regional sandy areas. Fish data from the period 2009-2012 were evaluated. Mainly I- and II-group Atlantic cod were present around the WARs; while the 0- and I-group dominated for pouting. For Atlantic cod, no differences in length were observed between sites, indicating that fitness was comparable at the WARs and in sandy areas. No significant differences in condition index were observed for pouting. At the WARs, they were slightly larger and stomach fullness was enhanced compared to the surrounding sandy areas. Also diet differed considerably among the sites. The outcome of the proxies indicate that fitness of pouting was slightly enhanced compared to the surrounding sandy areas. No evidence was obtained supporting the hypothesis that the WARs act as an ecological trap for Atlantic cod and pouting.


Kinetic studies on the CuO/gamma-Al2O3 sorbent regeneration by methane--topochemical approach.
CuO impregnated gamma-Al2O3 support provides convenient adsorption and regeneration characteristics. These features give the potential to regard this chemisorption process as more effective, feasible and widely accepted than lime and limestone scrubbing in the removal of SO2 from the outlet gases. Thermogravimetric tests on the regeneration of the CuO/gamma-Al2O3 exhausted sorbent (first stage of the regeneration, CuSO4-->Cu0) with methane were conducted. Commercially available 1/8" gamma-Al2O3 spheres, loaded with 5.8 wt % of Cu were investigated. The tests concerning the isothermal regeneration kinetics were performed at temperatures: T = 700, 727 and 750 K, while a 20 cm3 min(-1) flow of pure methane was used. To select the mechanism of the regeneration reaction, as well as to evaluate their kinetic parameters of the rate equations, the TGA data were compared with the series of theoretical topochemical kinetic models as advocated by Gardner, Hancock and Sharp's approach. The kinetic mechanism of the regeneration reaction in the initial stage of the process may be originally interpreted as the combination of both boundary-surface-controlled reaction (contracting sphere) and the first-order kinetics models. Various diffusion limited kinetic equations have proved useful for the description of the final stage of the process. Both proposed models (two kinetic and four diffusion ones) fit fairly well to the experimental data (in their limited validity ranges) obtained in all three temperature values studied.


New insights in Adipokinetic Hormone (AKH) precursor processing in Locusta migratoria obtained by capillary liquid chromatography-tandem mass spectrometry.
After translation, the AKH I and AKH II precursors form three dimeric constructs prior to further processing into the respective AKHs and three dimeric Adipokinetic Hormone Precursor Related Peptides or APRPs (two homodimers and one heterodimer). By capillary liquid chromatography-tandem mass spectrometry we demonstrate that the APRPs in Locusta migratoria are further processed to form two smaller neuropeptides: DAADFADPYSFL (residue 36 to 47 of the AKH I precursor) and YADPNADPMAFL (residue 34 to 45 of the AKH II precursor). The peptides are designated as Adipokinetic Hormone Joining Peptide 1 (AKH-JP I) and 2 (AKH-JP II) respectively. Within the AKH I and AKH II precursor molecules, the classic KK and RR processing sites separate the AKH-JPs from the AKH I and II respectively. At the carboxyterminus, both AKH-JP I and II are flanked by Tyr-Arg, a cleaving site not described before. Such an unusual cleavage site suggests the presence, in the corpora cardiaca, of specific convertases. The AKH-JP-II does not stimulate lipid release from the fat body nor does it stimulate glycogen phosphorylase activity, both key functions of AKH.


[Non-pharmacological therapies for language deficits in the agrammatic and logopenic variants of primary progressive aphasia: a literature review].
Primary progressive aphasia is a neurodegenerative condition characterised by a progressive and isolated disorder of expressive language, associated with atrophy of the left posterior frontoinsular region (nonfluent/agrammatic variant) or with atrophy of the left temporoparietal junction area (logopenic variant). This literature review reports studies about language therapies for these two variants of primary progressive aphasia. More precisely, the review presents the behavioral interventions and the augmentative/alternative communication tools reported in the literature to improve language performances or to compensate for language difficulties. Most of these studies reported that interventions are efficient. However, inconsistent results are found regarding maintenance of improvement and generalization to untreated language abilities. Other studies are still required to establish the clinical relevance of interventions for language and communication disorders in primary progressive aphasia. In these studies, the use of more ecological interventions focusing on the specific needs of people living with this disease should be specifically addressed.


Proton/hydrogen transfer affects the S-state-dependent microsecond phases of P680+ reduction during water splitting.
To investigate a possible coupling between P680+ reduction and hydrogen transfer, we studied the effects of H2O/D2O exchange on the P680+ reduction kinetics in the nano- and microsecond domains. We concentrated on studying the period-4 oscillatory (i.e., S-state-related) part of the reduction kinetics, by analyzing the differences between the P680+ reduction curves, rather than the full kinetics. Earlier observations that P680+ reduction kinetics have microsecond components were confirmed: the longest observable lifetime whose amplitude showed period-4 oscillations was 30 microseconds. We found that solvent isotope exchange left the nanosecond phases of the P680+ reduction unaltered. However, a significant effect on the oscillatory microsecond components was observed. We propose that, at least in the S0/S1 and S3/S0 transitions, hydrogen (proton) transfer provides an additional decrease in the free energy of the YZ+P680 state with respect to the YZP680+ state. This implies that relaxation of the state YZ+P680 is required for complete reduction of P680+ and for efficient water splitting. The kinetics of the P680+ reduction suggest that it is intraprotein proton/hydrogen rearrangement/transfer, rather than proton release to the bulk, which is occurring on the 1-30 microseconds time scale.


Metabolic and functional characterization of effects of developmental temperature in Drosophila melanogaster.
The ability of ectotherms to respond to changes in their thermal environment through plastic mechanisms is central to their adaptive capability. However, we still lack knowledge on the physiological and functional responses by which ectotherms acclimate to temperatures during development, and in particular, how physiological stress at extreme temperatures may counteract beneficial acclimation responses at benign temperatures. We exposed Drosophila melanogaster to 10 developmental temperatures covering their entire permissible temperature range. We obtained metabolic profiles and reaction norms for several functional traits: egg-to-adult viability, developmental time, and heat and cold tolerance. Females were more heat tolerant than males, whereas no sexual dimorphism was found in cold tolerance. A group of metabolites, mainly free amino acids, had linear reaction norms. Several energy-carrying molecules, as well as some sugars, showed distinct inverted U-shaped norms of reaction across the thermal range, resulting in a positive correlation between metabolite intensities and egg-to-adult viability. At extreme temperatures, low levels of these metabolites were interpreted as a response characteristic of costs of homeostatic perturbations. Our results provide novel insights into a range of metabolites reported to be central for the acclimation response and suggest several new candidate metabolites. Low and high temperatures result in different adaptive physiological responses, but they also have commonalities likely to be a result of the failure to compensate for the physiological stress. We suggest that the regulation of metabolites that are tightly connected to the performance curve is important for the ability of ectotherms to cope with variation in temperature.


Protein arginine methyltransferase 1-directed methylation of Kaposi sarcoma-associated herpesvirus latency-associated nuclear antigen.
The Kaposi sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA) is a multifunctional protein with roles in gene regulation and maintenance of viral latency. Post-translational modification of LANA is important for functional diversification. Here, we report that LANA is subject to arginine methylation by protein arginine methyltransferase 1 in vitro and in vivo. The major arginine methylation site in LANA was mapped to arginine 20. This site was mutated to either phenylalanine (bulky hydrophobic, constitutive methylated mimetic) or lysine (positively charged, non-arginine methylatable) residues. The significance of the methylation in LANA function was examined in both the isolated form and in the context of the viral genome through the generation of recombinant KSHV. In addition, authentic LANA binding sites on the KSHV episome in naturally infected cells were identified using a whole genome KSHV tiling array. Although mutation of the methylation site resulted in no significant difference in KSHV LANA subcellular localization, we found that the methylation mimetic mutation resulted in augmented histone binding in vitro and increased LANA occupancy at identified LANA target promoters in vivo. Moreover, a cell line carrying the methylation mimetic mutant KSHV showed reduced viral gene expression relative to controls both in latency and in the course of reactivation. These results suggest that residue 20 is important for modulation of a subset of LANA functions and properties of this residue, including the hydrophobic character induced by arginine methylation, may contribute to the observed effects.


DNA polymerase III of Mycoplasma pulmonis: isolation and characterization of the enzyme and its structural gene, polC.
Mycoplasmas have originated from Gram-positive bacteria via rapid degenerative evolution. The results of previous investigations of mycoplasmal DNA polymerases suggest that the process of evolution has wrought a major simplification of the typical Gram-positive bacterial DNA polymerase profile, reducing it from three exonuclease (exo)-positive enzymes to a single exo-negative species. The objective of this work was to rigorously investigate this suggestion, focusing on the evolutionary fate of DNA polymerase III (Pol III), the enzyme which Gram-positive bacteria specifically require for replicative DNA synthesis. The approach used Mycoplasma pulmonis as the model organism and exploited structural gene cloning, enzymology, and Pol III-specific inhibitors of the HPUra class as investigative tools. Our results indicate that M. pulmonis has strongly conserved a single copy of a structural gene homologous to polC, the Gram-positive bacterial gene encoding Pol III. M. pulmonis was found to possess a DNA polymerase that displays the size, primary structure, exonuclease activity, and level of HPUra sensitivity expected of a prototypical Gram-positive Pol III. The high level of sensitivity of M. pulmonis growth to Gram-positive Pol III-selective inhibitors of the HPUra type strongly suggests that Mycoplasma has conserved not only the basic structure of Pol III, but also its essential replicative function. Evidence for a second, HPUra-resistant polymerase activity in M. pulmonis is also described, indicating that the DNA polymerase composition of Mycoplasma is complex and closer to that of Gram-positive bacteria than previously thought.


Preparing for presymptomatic DNA testing for early onset Alzheimer's disease/cerebral haemorrhage and hereditary Pick disease.
The acceptability of presymptomatic testing in 21 people at 50% risk for the APP-692 mutation causing presenile Alzheimer's disease or cerebral haemorrhage resulting from cerebral amyloid angiopathy (FAD-CH), and in 43 people at 50% risk for hereditary Pick disease (HPD) was assessed. Neither group differed in demographic variables. Thirty-nine people (64%) in the whole group would request presymptomatic testing if it were clinically available, although two-thirds did not yet feel ready to take it. The most important reasons in the HPD and FAD-CH group for taking the test were: to further basic research (42% and 47%, respectively), informing children (47% and 50%, respectively), future planning (29% and 47%, respectively), and relieving uncertainty (46% and 27%, respectively). The most commonly cited effect of an unfavourable test result concerned increasing problems for spouses (75% and 76%, respectively) and children (61% and 57%, respectively). Most respondents denied that an unfavourable result would have adverse effects on personal mood or relationship. One-third of all respondents favoured prenatal testing where one of the parents had an increased risk for HPD or FAD-CH. Participants would encourage their offspring to have the test before starting a relationship (35%) and before family planning (44%). Thirty-seven percent of the respondents would encourage their children to opt for prenatal diagnosis. People at risk for HPD were significantly more preoccupied with the occurrence of potential symptoms in themselves, compared with those at risk for FAD-CH, reflecting the devastating impact that disinhibition in the affected patient has on the family. Our findings underline the need for adequate counselling and the availability of professional and community resources to deal with the impact of test results in subjects and their relatives.


[Comparative analysis of RFLP of mitochondrial DNA in Eastern Slavic populations in Russia].
Data on restriction fragment length polymorphism (for entire mtDNA molecules--BamHI, DraI, EcoRI, HindIII, PstI, PvuII, ScaI; for the 16,081-16,545 bp segment of mtDNA--AvaII, BamHI, EcoRV, HaeIII, HinfI, KpnI, RsaI, Sau3AI) in eastern Slavs of Magadan is presented. By Sau3AI/BclI digestion analysis, a new polymorphic variant of mtDNA in Caucasoid populations with the C-T nucleotide substitution in position 16147 bp was revealed. The absence of significant differences in mitotypic diversity of Slavic samples from Magadan (h = 0.921 in Russians, h = 0.898 in Ukrainians) was observed. By comparative analysis of mtDNA RFLP, the presence of genetic differences between eastern Slavic populations of Magadan, Tomsk, and the cities of the European region of Russia was demonstrated.


An experimental study of the open end correction coefficient for side branches within an acoustic tube.
The open end correction coefficient (OECC) of acoustic tubes has been widely investigated under a free-field condition. This study examines OECCs in confined regions, such as side branches within the vocal tract. To do this, a number of mechanical acoustic models are used to examine the effects of the angle of the branch axis and the proximity of the walls of the main tract to the open end of the branch. The OECC is estimated by matching both the peaks and troughs (i.e., spectral maxima and minima) of the computed and measured transfer functions for each model. The results indicate that the OECC of a side branch depends on L/D, where L is the cross dimension of the main tract at the branching point, and D is the branch diameter. For side branches connected to the main tract through a narrow neck, the OECC of each end of the neck is determined using the ratio of the radius of the neck to that of the adjacent section. Two empirical equations for evaluating the OECC within a tract are derived from the present study. Finally, the range of appropriate OECC values for estimating an accurate vocal tract transfer function is discussed, based on the results presented here and morphologic measurements reported previously.


County-level correlates of dental service utilization for low income pregnant women. Ecologic study of the North Carolina Medicaid for Pregnant Women (MPW) program.
Dental care utilization for low income pregnant women is met with challenges in the traditional dentist-centered model of care. County-level measures provide insights for policy and roles for stakeholders that extend beyond the dentist-patient relationship. We examined county-level data to generate hypotheses about factors that influence utilization of dental services in North Carolina's Medicaid for Pregnant Women (MPW) program. County-level Medicaid utilization data for dental services for 2014-2016 were pooled to get mean county estimates of dental utilization in the MPW program. Descriptive statistics and multivariate regression models of dental utilization and county-level measures are presented. Data used were collected by NC Child and the Robert Wood Johnson Foundation's County Health Rankings Reports. USDA Economic Research Service data were used to categorize counties in terms of Farming, Recreation, Persistent Poverty, and metro/non-metro status using Rural Urban Continuum Codes. Dental utilization ranged from 1-26% with a median of 8.5% across the 100 counties of North Carolina. Strong patterns linking utilization of dental services in the MPW program to contextual social measures of well-being emerged, specifically, increased reporting of child abuse and neglect, elevated infant mortality, poor quality of life, and worse ranking in years of potential life lost. Counties with persistent poverty had lower rates of dental utilization. Utilization of dental services in the MPW program is generally low. Patterns identify the potential for enhancing community-clinical linkages to improve birth outcomes and care coordination for pregnant women to enhance dental utilization in this population. Dental coverage in the Medicaid program in most states is administered separately from medical coverage. The separation of the funding mechanisms adds a further layer of complexity to care integration. Efforts to enhance dental care for pregnant women in the Medicaid program may benefit from policy that aligns incentives for care coordination within the community. Policy that extends the window of eligibility for dental benefits to 24 months after the birth of the child will help women complete the dental treatment that is needed. This also leverages the value of care coordination for community stakeholders from diverse child health sectors.


NOTCH1 activation in breast cancer confers sensitivity to inhibition of SUMOylation.
Breast cancer is genetically heterogeneous, and recent studies have underlined a prominent contribution of epigenetics to the development of this disease. To uncover new synthetic lethalities with known breast cancer oncogenes, we screened an epigenome-focused short hairpin RNA library on a panel of engineered breast epithelial cell lines. Here we report a selective interaction between the NOTCH1 signaling pathway and the SUMOylation cascade. Knockdown of the E2-conjugating enzyme UBC9 (UBE2I) as well as inhibition of the E1-activating complex SAE1/UBA2 using ginkgolic acid impairs the growth of NOTCH1-activated breast epithelial cells. We show that upon inhibition of SUMOylation NOTCH1-activated cells proceed slower through the cell cycle and ultimately enter apoptosis. Mechanistically, activation of NOTCH1 signaling depletes the pool of unconjugated small ubiquitin-like modifier 1 (SUMO1) and SUMO2/3 leading to increased sensitivity to perturbation of the SUMOylation cascade. Depletion of unconjugated SUMO correlates with sensitivity to inhibition of SUMOylation also in patient-derived breast cancer cell lines with constitutive NOTCH pathway activation. Our investigation suggests that SUMOylation cascade inhibitors should be further explored as targeted treatment for NOTCH-driven breast cancer.


Reproductive trade-offs may moderate the impact of Gyrodactylus salaris in warmer climates.
Gyrodactylus salaris is a notifiable freshwater ectoparasite of salmonids. Its primary host is Atlantic salmon (Salmo salar), upon which infections can cause death, and have led to massive declines in salmon numbers in Norway, where the parasite is widespread. Different strains of S. salar vary in their susceptibility, with Atlantic strains (such as those found in Norway) exhibiting no resistance to the parasite, and Baltic strains demonstrating an innate resistance sufficient to regulate parasite numbers on the host causing it to either die out or persist at a low level. In this study, Leslie matrix and compartmental models were used to generate data that demonstrated the population growth of G. salaris on an individual host is dependent on the total number of offspring per parasite, its longevity and the timing of its births. The data demonstrated that the key factor determining the rate of G. salaris population growth is the time at which the parasite first gives birth, with rapid birth rate giving rise to large population size. Furthermore, it was shown that though the parasite can give birth up to four times, only two births are required for the population to persist as long as the first birth occurs before a parasite is three days old. As temperature is known to influence the timing of the parasite's first birth, greater impact may be predicted if introduced to countries with warmer climates than Norway, such as the UK and Ireland which are currently recognised to be free of G. salaris. However, the outputs from the models developed in this study suggest that temperature induced trade-offs between the total number of offspring the parasite gives birth to and the first birth timing may prevent increased population growth rates over those observed in Norway.


Effect of Alcohol and Tea on Solubility of Soft-liner and Polymethyl Methacrylate Resin: An In Vitro Study.
To evaluate solubility of soft denture liner material and acrylic denture base resin when stored in 8% and 50% concentration of alcohol and tea(with milk and green tea) at an interval of 4,7,11 and 15 days. An in vitro study wasdone on 75 standardized samples in disk form (15 mm × 2 mm), each for soft-liner and acrylic denture base resin. Samples were divided into 5 groups (15 per group/per material) and stored in distilled water (A), 8% alcohol (B), 50% alcohol (C), tea with milk (D) and green tea (E). Solubility was determined at each time interval by dividing difference of weight (taken after drying the sample in a desiccator) from day 1 divided by surface area of the specimen. For each day (i.e., 4, 7, 11 and 15),one-way analysis of variance (ANOVA) test was used to determine if the distribution of mean solubility was similar in five groups followed by post-hoc Tukey's test for pair-wise comparisons. Mean solubility of soft-liner was the highest tea with milk (D) followed by green tea (E), then 50% and 8 % alcohol (C and B) and was least in group A at each time of measurement. Mean solubility of an acrylic resin was highest for 8% alcohol (B) and all other groups it was similar. This study shows increased solubility for soft-liners when immersed in tea with milk, green tea, and alcohol at 8% and 50% concentration. The solubility of acrylic resin also increases at 8% alcohol concentration. Drinks/beverages used in our study are commonly consumed, the results of this study caution for restricting the frequency of intake. However, this needs to be confirmed by in-vivo studies designed to prove the association of denture life with the consumption pattern of these drinks/ beverages.


Protein-Based Vaccine Protect Against Piscirickettsia salmonis in Atlantic Salmon (Salmo salar).
An effective and economical vaccine against the Piscirickettsia salmonis pathogen is needed for sustainable salmon farming and to reduce disease-related economic losses. Consequently, the aquaculture industry urgently needs to investigate efficient prophylactic measures. Three protein-based vaccine prototypes against Piscirickettsia salmonis were prepared from a highly pathogenic Chilean isolate. Only one vaccine effectively protected Atlantic salmon (Salmo salar), in correlation with the induction of Piscirickettsia-specific IgM antibodies and a high induction of transcripts encoding pro-inflammatory cytokines (i.e., Il-1β and TNF-α). In addition, we studied the proteome fraction protein of P. salmonis strain Austral-005 using multidimensional protein identification technology. The analyzes identified 87 proteins of different subcellular origins, such as the cytoplasmic and membrane compartment, where many of them have virulence functions. The other two prototypes activated only the innate immune responses, but did not protect Salmo salar against P. salmonis. These results suggest that the knowledge of the formulation of vaccines based on P. salmonis proteins is useful as an effective therapy, this demonstrates the importance of the different research tools to improve the study of the different immune responses, resistance to diseases in the Atlantic salmon. We suggest that this vaccine can help prevent widespread infection by P. salmonis, in addition to being able to be used as a booster after a primary vaccine to maintain high levels of circulating protective antibodies, greatly helping to reduce the economic losses caused by the pathogen.


Synaptic proteins associated with cognitive performance and neuropathology in older humans revealed by multiplexed fractionated proteomics.
Alzheimer's disease (AD) is defined by the presence of abundant amyloid-β (Aβ) and tau neuropathology. While this neuropathology is necessary for AD diagnosis, it is not sufficient for causing cognitive impairment. Up to one third of community dwelling older adults harbor intermediate to high levels of AD neuropathology at death yet demonstrate no significant cognitive impairment. Conversely, there are individuals who exhibit dementia with no gross explanatory neuropathology. In prior studies, synapse loss correlated with cognitive impairment. To understand how synaptic composition changes in relation to neuropathology and cognition, multiplexed liquid chromatography mass-spectrometry was used to quantify enriched synaptic proteins from the parietal association cortex of 100 subjects with contrasting levels of AD pathology and cognitive performance. 123 unique proteins were significantly associated with diagnostic category. Functional analysis showed enrichment of serotonin release and oxidative phosphorylation categories in normal (cognitively unimpaired, low neuropathology) and "resilient" (unimpaired despite AD pathology) individuals. In contrast, frail individuals, (low pathology, impaired cognition) showed a metabolic shift towards glycolysis and increased presence of proteasome subunits.


Fieldmap-free retrospective registration and distortion correction for EPI-based functional imaging.
We describe a method for correcting the distortions present in echo planar images (EPI) and registering the EPI to structural MRI. A fieldmap is predicted from an air / tissue segmentation of the MRI using a perturbation method and subsequently used to unwarp the EPI data. Shim and other missing parameters are estimated by registration. We obtain results that are similar to those obtained using fieldmaps, however neither fieldmaps, nor knowledge of shim coefficients is required.


Causal Discovery and Forecasting in Nonstationary Environments with State-Space Models.
In many scientific fields, such as economics and neuroscience, we are often faced with nonstationary time series, and concerned with both finding causal relations and forecasting the values of variables of interest, both of which are particularly challenging in such nonstationary environments. In this paper, we study causal discovery and forecasting for nonstationary time series. By exploiting a particular type of state-space model to represent the processes, we show that nonstationarity helps to identify causal structure and that forecasting naturally benefits from learned causal knowledge. Specifically, we allow changes in both causal strengths and noise variances in the nonlinear state-space models, which, interestingly, renders both the causal structure and model parameters identifiable. Given the causal model, we treat forecasting as a problem in Bayesian inference in the causal model, which exploits the timevarying property of the data and adapts to new observations in a principled manner. Experimental results on synthetic and real-world data sets demonstrate the efficacy of the proposed methods.


Pain sensitivity and analgesic effects of mindful states in Zen meditators: a cross-sectional study.
To investigate pain perception and the potential analgesic effects of mindful states in experienced Zen meditators. Highly trained Zen meditators (n = 13; >1000 hours of practice) and age/gender-matched control volunteers (n = 13) received individually adjusted thermal stimuli to elicit moderate pain on the calf. Conditions included: a) baseline-1: no task; b) concentration: attend exclusively to the calf; c) mindfulness: attend to the calf and observe, moment to moment, in a nonjudgmental manner; and d) baseline-2: no task. Meditators required significantly higher temperatures to elicit moderate pain (meditators: 49.9 degrees C; controls: 48.2 degrees C; p = .01). While attending "mindfully," meditators reported decreases in pain intensity whereas control subjects showed no change from baseline. The concentration condition resulted in increased pain intensity for controls but not for meditators. Changes in pain unpleasantness generally paralleled those found in pain intensity. In meditators, pain modulation correlated with slowing of the respiratory rate and with greater meditation experience. Covariance analyses indicated that mindfulness-related changes could be partially explained by changes in respiratory rates. Finally, the meditators reported higher tendencies to observe and be nonreactive of their own experience as measured on the Five Factor Mindfulness Questionnaire; these factors correlated with individual differences in respiration. These results indicated that Zen meditators have lower pain sensitivity and experience analgesic effects during mindful states. Results may reflect cognitive/self-regulatory skills related to the concept of mindfulness and/or altered respiratory patterns. Prospective studies investigating the effects of meditative training and respiration on pain regulation are warranted.


Field dependence and the differentiation of affective states.
The extent to which anxiety, irritability and depression were differentiated as separate entities associated with characteristic patterns of somatic and cognitive symptoms by field dependent (FD) and field independent (FI) normal female subjects was studied with the Hidden Figures Test and Unpleasant Emotions Questionnaire. In the FI group the correlations between the three emotions were low and non-significant, reflecting a clear-cut differentiation in symptom configuration, as shown by psychiatrists. In the FD group the inter-correlations were significant and positive, corresponding to relatively poor symptom differentiation, comparable to that of a psychiatric patient group. This suggests that the cognitive style variable of field dependence may underly differences in symptom differentiation associated with psychiatrist/patient differences and, more generally, with social class and sex differences.


Nuclear medicine activity in the United Kingdom.
A survey of the extent of diagnostic and therapeutic nuclear medicine procedures in the UK has been conducted, and information collected on the types of imaging equipment employed and the typical activities of radiopharmaceuticals administered to patients. A total of 380,000 administrations took place in 1982, corresponding to approximately 6.8 per thousand head of population. 84% were imaging investigations, 13% were non-imaging diagnostic procedures and about 3% were for therapy. Bone scans accounted for 25% of all procedures and 99Tcm was the radionuclide of choice for 75% of investigations. Gamma cameras are superseding rectilinear scanners and most are being purchased together with dedicated image processing computers. Their average annual workload is 922 patients per year. There was considerable variation between the typical administered activities reported by different hospitals for the same procedure, and in some cases the figures reported exceeded the maximum usual activities recommended by the Administration of Radioactive Substances Advisory Committee.


Computer-Assisted Learning Applications in Health Educational Informatics: A Review.
Computer-assisted learning (CAL) as a health informatics application is a useful tool for medical students in the era of expansive knowledge bases and the increasing need for and the consumption of automated and interactive systems. As the scope and breadth of medical knowledge expand, the need for additional learning outside of lecture hours is becoming increasingly important. CAL can be an impactful adjunct to conventional methods that currently exist in the halls of learning. There is an increasing body of literature that suggests that CAL should be a commonplace and the recommended method of learning for medical students. Factors such as technical issues that hinder the performance of CAL are also evaluated. We conclude by encouraging the use of CAL by medical students as a highly beneficial method of learning that complements and enhances lectures and provides intuitive, interactive modulation of a self-paced curriculum based on the individual's academic abilities.


Occurrence and expression of novel methyl-coenzyme M reductase gene (mcrA) variants in hot spring sediments.
Recent discoveries have shown that the marker gene for anaerobic methane cycling (mcrA) is more widespread in the Archaea than previously thought. However, it remains unclear whether novel mcrA genes associated with the Bathyarchaeota and Verstraetearchaeota are distributed across diverse environments. We examined two geochemically divergent but putatively methanogenic regions of Yellowstone National Park to investigate whether deeply-rooted archaea possess and express novel mcrA genes in situ. Small-subunit (SSU) rRNA gene analyses indicated that Bathyarchaeota were predominant in seven of ten sediment layers, while the Verstraetearchaeota and Euryarchaeota occurred in lower relative abundance. Targeted amplification of novel mcrA genes suggested that diverse taxa contribute to alkane cycling in geothermal environments. Two deeply-branching mcrA clades related to Bathyarchaeota were identified, while highly abundant verstraetearchaeotal mcrA sequences were also recovered. In addition, detection of SSU rRNA and mcrA transcripts from one hot spring suggested that predominant Bathyarchaeota were also active, and that methane cycling genes are expressed by the Euryarchaeota, Verstraetearchaeota, and an unknown lineage basal to the Bathyarchaeota. These findings greatly expand the diversity of the key marker gene for anaerobic alkane cycling and outline the need for greater understanding of the functional capacity and phylogenetic affiliation of novel mcrA variants.


Infection with Syphacia obvelata (pinworm) induces protective Th2 immune responses and influences ovalbumin-induced allergic reactions.
Infections with pinworms are common in rodent animal facilities. In this study, we show the consequence of an outbreak in a transgenic barrier facility of infection by Syphacia obvelata, a murine pinworm gastrointestinal nematode. Immune responses were defined in experimental infection studies with BALB/c mice. Infection with S. obvelata induced a transient Th2-type immune response with elevated interleukin 4 (IL-4), IL-5, and IL-13 cytokine production and parasite-specific immunoglobulin G1 (IgG1). In contrast, BALB/c mice deficient in IL-13, IL-4/13, or the IL-4 receptor alpha chain showed chronic disease, with a >100-fold higher parasite burden, increased gamma interferon production, parasite-specific IgG2b, and a default Th2 response. Interestingly, infected IL-4-/- BALB/c mice showed only slightly elevated parasite burdens compared to the control mice, suggesting that IL-13 plays the dominant role in the control of S. obvelata. The influence that pinworm infection has on the allergic response to a dietary antigen was found to be important. Helminth-infected mice immunized against ovalbumin (Ova) elicited more severe anaphylactic shock with reduced Ova-specific IL-4 and IL-5 than did noninfected controls, demonstrating that S. obvelata infection is able to influence nonrelated laboratory experiments. The latter outcome highlights the importance of maintaining mice for use as experimental models under pinworm-free conditions.


Forecasting Short-Term Traffic Flow by Fuzzy Wavelet Neural Network with Parameters Optimized by Biogeography-Based Optimization Algorithm.
Forecasting short-term traffic flow is a key task of intelligent transportation systems, which can influence the traveler behaviors and reduce traffic congestion, fuel consumption, and accident risks. This paper proposes a fuzzy wavelet neural network (FWNN) trained by improved biogeography-based optimization (BBO) algorithm for forecasting short-term traffic flow using past traffic data. The original BBO is enhanced by the ring topology and Powell's method to advance the exploration capability and increase the convergence speed. Our presented approach combines the strengths of fuzzy logic, wavelet transform, neural network, and the heuristic algorithm to detect the trends and patterns of transportation data and thus has been successfully applied to transport forecasting. Other different forecasting methods, including ANN-based model, FWNN-based model, and WNN-based model, are also developed to validate the proposed approach. In order to make the comparisons across different methods, the performance evaluation is based on root-mean-squared error (RMSE), mean absolute percentage error (MAPE), and correlation coefficient (R). The performance indexes show that the FWNN model achieves lower RMSE and MAPE, as well as higher R, indicating that the FWNN model is a better predictor.


Verocytotoxin-producing Escherichia coli O157 on a farm open to the public: outbreak investigation and longitudinal bacteriological study.
Verocytotoxin-producing Escherichia coli (VTEC) O157 phage type 2 (PT2) was isolated from three calves and two goats on a farm open to the public. Phenotypic and DNA-based typing showed that the strains were identical or very closely related to those obtained from an outbreak of VTEC O157 infection in two separate family groups who visited the farm. No VTEC O157 PT2 was isolated again from the farm during a 12-month longitudinal bacteriological study undertaken after the infected animals had been removed. However, phenotypically and genotypically indistinguishable VTEC O157 PT2/28 strains were detected in two of 474 faecal samples collected at monthly visits from 15 species of animals of various ages. The two isolates were obtained from calves from different sources sampled 146 days apart, suggesting that the infection had persisted on the farm although it was not detected in the other species. The same strain was subsequently isolated from another calf housed in the same pen as one of the infected calves. The longest period during which the organism was excreted was seven days. No VTEC O157 was isolated either from 204 replacement animals (including 138 orphan lambs and 10 calves) brought in from various sources, and sampled while they were kept in isolation for two weeks before being introduced to the farm, or from environmental samples. During the study a visitor became ill with VTEC O157 PT2. However, the isolate was distinct from those recovered from the farm and there was no evidence to suggest that the visit was the source of the infection.


Nanoscale coaxial focused electrohydrodynamic jet printing.
Controlled patterning of nanostructures at desired positions is of great importance for high-performance M/NEMS devices. Here, we demonstrate a high-resolution, high-speed and cost-effective fabrication method, named coaxial focused electrohydrodynamic jet printing, to print functional nanostructures. A coaxial needle was designed and developed; a functional ink and high viscosity liquid are applied in the inner and outer needle, respectively. Under optimised conditions, a stable coaxial jet is formed; then, the electrical shearing force and electrical field induce viscous shearing force and internal pressure that are jointly applied on the inner functional ink, focusing the inner jet on the nanoscale. Using this stable coaxial jet with a nano-jet inside it, nanostructures with highly aligned nanowire arrays, nano-freebeams and nano-cantilever beams down to the scale of 40 nm were directly printed. The needle size was 130 μm, and the ratio of the sizes of the needle and the printed structure was as high as 3250/1. This technique realizes the controllable printing of nanoscale structures with the use of a one hundred micrometer-sized needle. The printed PZT nanostructures exhibit pure perovskite structures and distinct piezoelectric responses.


Determinants of smoking initiation among women in five European countries: a cross-sectional survey.
The rate of smoking and lung cancer among women is rising in Europe. The primary aim of this study was to determine why women begin smoking in five different European countries at different stages of the tobacco epidemic and to determine if smoking is associated with certain characteristics and/or beliefs about smoking. A cross-sectional telephone survey on knowledge and beliefs about tobacco was conducted as part of the Women in Europe Against Lung Cancer and Smoking (WELAS) Project. A total of 5,000 adult women from France, Ireland, Italy, Czech Republic, and Sweden were interviewed, with 1,000 from each participating country. All participants were asked questions about demographics, knowledge and beliefs about smoking, and their tobacco use background. Current and former smokers also were asked questions about smoking initiation. Basic statistics on the cross-sectional data was reported with chi-squared and ANOVA p-values. Logistic regression was used to analyze ever versus never smokers. Linear regression analyses were used to analyze age of smoking initiation. Being older, being divorced, having friends/family who smoke, and having parents who smoke were all significantly associated with ever smoking, though the strength of the associations varied by country. The most frequently reported reason for initiation smoking was friend smoking, with 62.3% of ever smokers reporting friends as one of the reasons why they began smoking. Mean age of smoking initiation was 18.2 years and over 80% of participants started smoking by the age of 20. The highest levels of young initiators were in Sweden with 29.3% of women initiating smoking at age 14-15 and 12.0% initiating smoking younger than age 14. The lowest level of young initiators was in the Czech Republic with 13.7% of women initiating smoking at age 14-15 and 1.4% of women initiating smoking younger than age 14. Women who started smoking because their friends smoked or to look 'cool' were more likely to start smoking at a younger age. Women who started smoking to manage stress or to feel less depressed were more likely to start smoking at an older age. In all five participating countries, friends were the primary factor influencing ever smoking, especially among younger women. The majority of participants began smoking in adolescence and the average reported age of smoking initiation was youngest in Sweden and oldest in the Czech Republic.


Release of active cytokinin by a beta-glucosidase localized to the maize root meristem.
A beta-glucoside encoded by a cloned Zea mays complementary DNA (Zm-p60.1) cleaved the biologically inactive hormone conjugates cytokinin-O-glucosides and kinetin-N3-glucoside, releasing active cytokinin. Tobacco protoplasts that transiently expressed Zm-p60.1 could use the inactive cytokinin glucosides to initiate cell division. The ability of protoplasts to sustain growth in response to cytokinin glucosides persisted indefinitely after the likely disappearance of the expression vector. In the roots of maize seedlings, Zm-p60.1 was localized to the meristematic cells and may function in vivo to supply the developing maize embryo with active cytokinin.


Testing for effects of climate change on competitive relationships and coexistence between two bird species.
Climate change is expected to have profound ecological effects, yet shifts in competitive abilities among species are rarely studied in this context. Blue tits (Cyanistes caeruleus) and great tits (Parus major) compete for food and roosting sites, yet coexist across much of their range. Climate change might thus change the competitive relationships and coexistence between these two species. Analysing four of the highest-quality, long-term datasets available on these species across Europe, we extend the textbook example of coexistence between competing species to include the dynamic effects of long-term climate variation. Using threshold time-series statistical modelling, we demonstrate that long-term climate variation affects species demography through different influences on density-dependent and density-independent processes. The competitive interaction between blue tits and great tits has shifted in one of the studied sites, creating conditions that alter the relative equilibrium densities between the two species, potentially disrupting long-term coexistence. Our analyses show that long-term climate change can, but does not always, generate local differences in the equilibrium conditions of spatially structured species assemblages. We demonstrate how long-term data can be used to better understand whether (and how), for instance, climate change might change the relationships between coexisting species. However, the studied populations are rather robust against competitive exclusion.


Utility of Left Atrial Expansion Index and Stroke Volume in Management of Chronic Systolic Heart Failure.
Titration of evidence-based medications, important for treating heart failure (HF), is often underdosed by symptom-guided treatment. The aim of this study was to investigate, using echocardiographic parameters, stroke volume and left ventricular (LV) filling pressure to guide up-titration of medications, increasing prognostic benefits. A total of 765 patients with chronic HF and severely reduced LV ejection fractions (<35%), referred from 2008 to 2016, were prospectively studied. Echocardiographic guidance was performed in 149 patients. LV filling pressure was assessed by left atrial expansion index, and stroke volume was estimated from diameter and time-velocity integral in the LV outflow tract. Up-titration of evidence-based medications and adjustment for side effects or worsening clinical conditions according to those parameters were performed. Propensity score matching was used to match pairs of patients with (n = 110) or without (n = 110) echocardiographic guidance. End points were 4-year frequencies of HF hospitalization and all-cause mortality. During a mean follow-up time of 4.1 years, rates of adverse events were 58 (52.7%) with no echocardiographic guidance and 36 (32.7%) with echocardiographic guidance (P < .0001). Echocardiography provided effective guidance to reduce prescribing frequency and dose of diuretics and to promote evidence-based medication prescription. It reduced HF rehospitalization and all-cause mortality. By multivariate analysis, prognostic improvement was associated with up-titration of medications with echocardiographic guidance. There was a statistically significant difference in long-term prognosis between propensity score-matched pairs of patients with chronic severe HF with and without echocardiographic guidance. These findings need further validation in large prospective clinical trials.


Re-examination of the relationship between marine virus and microbial cell abundances.
Marine viruses are critical drivers of ocean biogeochemistry, and their abundances vary spatiotemporally in the global oceans, with upper estimates exceeding 10(8) per ml. Over many years, a consensus has emerged that virus abundances are typically tenfold higher than microbial cell abundances. However, the true explanatory power of a linear relationship and its robustness across diverse ocean environments is unclear. Here, we compile 5,671 microbial cell and virus abundance estimates from 25 distinct marine surveys and find substantial variation in the virus-to-microbial cell ratio, in which a 10:1 model has either limited or no explanatory power. Instead, virus abundances are better described as nonlinear, power-law functions of microbial cell abundances. The fitted scaling exponents are typically less than 1, implying that the virus-to-microbial cell ratio decreases with microbial cell density, rather than remaining fixed. The observed scaling also implies that viral effect sizes derived from 'representative' abundances require substantial refinement to be extrapolated to regional or global scales.