The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation.
Despite recent advances, cytomegalovirus (CMV) infections remain one of the most common complications affecting solid organ transplant recipients, conveying higher risks of complications, graft loss, morbidity, and mortality. Research in the field and development of prior consensus guidelines supported by The Transplantation Society has allowed a more standardized approach to CMV management. An international multidisciplinary panel of experts was convened to expand and revise evidence and expert opinion-based consensus guidelines on CMV management including prevention, treatment, diagnostics, immunology, drug resistance, and pediatric issues. Highlights include advances in molecular and immunologic diagnostics, improved understanding of diagnostic thresholds, optimized methods of prevention, advances in the use of novel antiviral therapies and certain immunosuppressive agents, and more savvy approaches to treatment resistant/refractory disease. The following report summarizes the updated recommendations.


Root hydrotropism is controlled via a cortex-specific growth mechanism.
Plants can acclimate by using tropisms to link the direction of growth to environmental conditions. Hydrotropism allows roots to forage for water, a process known to depend on abscisic acid (ABA) but whose molecular and cellular basis remains unclear. Here we show that hydrotropism still occurs in roots after laser ablation removed the meristem and root cap. Additionally, targeted expression studies reveal that hydrotropism depends on the ABA signalling kinase SnRK2.2 and the hydrotropism-specific MIZ1, both acting specifically in elongation zone cortical cells. Conversely, hydrotropism, but not gravitropism, is inhibited by preventing differential cell-length increases in the cortex, but not in other cell types. We conclude that root tropic responses to gravity and water are driven by distinct tissue-based mechanisms. In addition, unlike its role in root gravitropism, the elongation zone performs a dual function during a hydrotropic response, both sensing a water potential gradient and subsequently undergoing differential growth.


Evaluation of a Standardized Extract from Morus alba against α-Glucosidase Inhibitory Effect and Postprandial Antihyperglycemic in Patients with Impaired Glucose Tolerance: A Randomized Double-Blind Clinical Trial.
To evaluate the antihyperglycemic effect of a standardized extract of the leaves of Morus alba (SEMA), the present study was designed to investigate the α-glucosidase inhibitory effect and acute single oral toxicity as well as evaluate blood glucose reduction in animals and in patients with impaired glucose tolerance in a randomized double-blind clinical trial. SEMA was found to inhibit α-glucosidase at a fourfold higher level than the positive control (acarbose), in a concentration-dependent manner. Moreover, blood glucose concentration was suppressed by SEMA in vivo. Clinical signs and weight changes were observed when conducting an evaluation of the acute toxicity of SEMA through a single-time administration, with clinical observation conducted more than once each day. After administration of the SEMA, observation was for 14 days; all of the animals did not die and did not show any abnormal symptoms. In addition, the inhibitory effects of rice coated with SEMA were evaluated in a group of impaired glucose tolerance patients on postprandial glucose and a group of normal persons, and results showed that SEMA had a clear inhibitory effect on postprandial hyperglycemia in both groups. Overall, SEMA showed excellent potential in the present study as a material for improving postprandial hyperglycemia.


Common neural correlates of intertemporal choices and intelligence in adolescents.
Converging behavioral evidence indicates that temporal discounting, measured by intertemporal choice tasks, is inversely related to intelligence. At the neural level, the parieto-frontal network is pivotal for complex, higher-order cognitive processes. Relatedly, underrecruitment of the pFC during a working memory task has been found to be associated with steeper temporal discounting. Furthermore, this network has also been shown to be related to the consistency of intertemporal choices. Here we report an fMRI study that directly investigated the association of neural correlates of intertemporal choice behavior with intelligence in an adolescent sample (n = 206; age 13.7-15.5 years). After identifying brain regions where the BOLD response during intertemporal choice was correlated with individual differences in intelligence, we further tested whether BOLD responses in these areas would mediate the associations between intelligence, the discounting rate, and choice consistency. We found positive correlations between BOLD response in a value-independent decision network (i.e., dorsolateral pFC, precuneus, and occipital areas) and intelligence. Furthermore, BOLD response in a value-dependent decision network (i.e., perigenual ACC, inferior frontal gyrus, ventromedial pFC, ventral striatum) was positively correlated with intelligence. The mediation analysis revealed that BOLD responses in the value-independent network mediated the association between intelligence and choice consistency, whereas BOLD responses in the value-dependent network mediated the association between intelligence and the discounting rate. In summary, our findings provide evidence for common neural correlates of intertemporal choice and intelligence, possibly linked by valuation as well as executive functions.


Early detection of unhealthy behaviors, the prevalence and receipt of antiviral treatment for disabled adult hepatitis B and C carriers.
Evidence indicates that hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are the leading causes of liver cirrhosis and hepatocellular carcinoma. Antiviral treatments have recently been reported as successful cures. However, the prevalence rates of HBV or HCV infection, unhealthy behaviors and receipt of adequate treatment in disabled adults have not been described. The aim of this study was to examine the prevalence of HBV or HCV carriers, receipt of antiviral treatment, and early detection of unhealthy behaviors in disabled adults in Taiwan. A population-based, cross-sectional study was conducted between July and December 2013 with 845 community-dwelling adults with disabilities aged >20 years. Statistical analyses included descriptive statistics, Chi-squared tests, and stepwise regression analysis. The prevalence of HBV and HCV infections was 12.9 and 14.1 %, respectively. HCV carriers tended to be older (p < 0.001) and with a lower education (p < 0.001). The majority of HBV/HCV carriers did not know the type of hepatitis infection and did not receive adequate antiviral treatment. After adjusting for potential confounding variables, regression analysis showed that the factors significantly associated with elevated liver function were HCV infection (p < 0.001), HBV infection (p = 0.001), high fasting blood glucose levels (p = 0.001), overweight (p = 0.003), older age (p = 0.027), and alcohol drinking (p = 0.028). There was a high prevalence of HCV infection among adults with disabilities; few received adequate antiviral treatment or early detection of unhealthy behaviors for the prevention of liver cancer. Clinicians can provide health education to help the participants and caregivers better understand the relationships between specific risk factors and liver health and can encourage HBV and HCV carriers to undergo annual physical check-ups and receive adequate treatment, as covered by the national health insurance.


Patients' perceptions of communication with the health care team during chemotherapy for the first recurrence of ovarian cancer.
The aim of this study was to explore what women with recurrent ovarian cancer perceived as important in their communication with the health care team. Interviews were conducted with 12 women at the end of chemotherapy treatment at a department of gynecological oncology in central Sweden. The interviews were subjected to qualitative content analysis. The findings stress the importance for the health care team to offer each woman the opportunity for support in becoming familiar with the disease. This theme of becoming familiar with the disease is underpinned by four sub-themes: being acknowledged as a unique person, getting help to make sense of information regarding the disease and its treatment, having the opportunity to be involved and to share responsibility, and feeling confident that medical expertise was adequate. Becoming familiar with the disease was expressed as a process of understanding and assimilating the whole new situation. To achieve familiarity, the women needed help from the health care team to make sense of the information they received. They stressed the importance of being able to influence encounters with health professionals, in accordance with their own perspectives. Being acknowledged as a unique person was a prerequisite to achieve familiarity. Also important to the women was having the opportunity to share responsibility for their care and lives with someone from the health care team. Helping women with recurrence of ovarian cancer attain a sense of familiarity with the disease should be an important priority for health care providers.


Segmentation of pulmonary nodules in thoracic CT scans: a region growing approach.
This paper presents an efficient algorithm for segmenting different types of pulmonary nodules including high and low contrast nodules, nodules with vasculature attachment, and nodules in the close vicinity of the lung wall or diaphragm. The algorithm performs an adaptive sphericity oriented contrast region growing on the fuzzy connectivity map of the object of interest. This region growing is operated within a volumetric mask which is created by first applying a local adaptive segmentation algorithm that identifies foreground and background regions within a certain window size. The foreground objects are then filled to remove any holes, and a spatial connectivity map is generated to create a 3-D mask. The mask is then enlarged to contain the background while excluding unwanted foreground regions. Apart from generating a confined search volume, the mask is also used to estimate the parameters for the subsequent region growing, as well as for repositioning the seed point in order to ensure reproducibility. The method was run on 815 pulmonary nodules. By using randomly placed seed points, the approach was shown to be fully reproducible. As for acceptability, the segmentation results were visually inspected by a qualified radiologist to search for any gross miss-segmentation. 84% of the first results of the segmentation were accepted by the radiologist while for the remaining 16% nodules, alternative segmentation solutions that were provided by the method were selected.


Correlates of T-cell-mediated viral control and phenotype of CD8(+) T cells in HIV-2, a naturally contained human retroviral infection.
While a significant proportion of HIV-2-infected individuals are asymptomatic and maintain undetectable viral loads (controllers), 15% to 20% progress to AIDS and are predicted by detectable viremia. Identifying immune correlates that distinguish these 2 groups should provide insights into how a potentially pathogenic retrovirus can be naturally controlled. We performed a detailed study of HIV-2-specific cellular responses in a unique community cohort in Guinea-Bissau followed for over 2 decades. T-cell responses were compared between controllers (n = 33) and viremic subjects (n = 27) using overlapping peptides, major histocompatibility complex class I tetramers, and multiparameter flow cytometry. HIV-2 viral control was significantly associated with a high-magnitude, polyfunctional Gag-specific CD8(+) T-cell response but not with greater perforin upregulation. This potentially protective HIV-2-specific response is surprisingly narrow. HIV-2 Gag-specific CD8(+) T cells are at an earlier stage of differentiation than cytomegalovirus-specific CD8(+) T-cells, do not contain high levels of cytolytic markers, and exhibit low levels of activation and proliferation, representing distinct properties from CD8(+) T cells associated with HIV-1 control. These data reveal the potential T-cell correlates of HIV-2 control and the detailed phenotype of virus-specific CD8(+) T cells in a naturally contained retroviral infection.


Radiofrequency applications to dorsal root ganglia: a literature review.
Application of radiofrequency currents to the dorsal root ganglia, in the treatment of various pain syndromes, has been clinically practiced for more than 30 yr. The clinical efficacy and the safety of this technique, however, remain poorly understood. The authors reviewed the literature on this modality of pain relief to determine its clinical efficacy, safety, and mechanisms of action. The two modalities in common clinical use were pulsed and continuous mode radiofrequency. These techniques were generally found to be safe, and the majority of the observational studies reported their clinical efficacy. Five randomized controlled trials evaluated their clinical use; these trials were relatively short-termed and small in size, and their results were variable. The mechanism of action of these techniques was unclear. Larger controlled clinical trials evaluating the long-term effects of these techniques and basic science research to determine their precise mode of action are needed.


Stroke warning campaigns: delivering better patient outcomes? A systematic review.
Patient delay in presenting to hospital with stroke symptoms remains one of the major barriers to thrombolysis treatment, leading to its suboptimal use internationally. Educational interventions such as mass media campaigns and community initiatives aim to reduce patient delays by promoting the signs and symptoms of a stroke, but no consistent evidence exists to show that such interventions result in appropriate behavioral responses to stroke symptoms. A systematic literature search and narrative synthesis were conducted to examine whether public educational interventions were successful in the reduction of patient delay to hospital presentation with stroke symptoms. Three databases, MEDLINE, CINAHL, and PsycINFO, were searched to identify quantitative studies with measurable behavioral end points, including time to hospital presentation, thrombolysis rates, ambulance use, and emergency department (ED) presentations with stroke. Fifteen studies met the inclusion criteria: one randomized controlled trial, two time series analyses, three controlled before and after studies, five uncontrolled before and after studies, two retrospective observational studies, and two prospective observational studies. Studies were heterogeneous in quality; thus, meta-analysis was not feasible. Thirteen studies examined prehospital delay, with ten studies reporting a significant reduction in delay times, with a varied magnitude of effect. Eight studies examined thrombolysis rates, with only three studies reporting a statistically significant increase in thrombolysis administration. Five studies examined ambulance usage, and four reported a statistically significant increase in ambulance transports following the intervention. Three studies examining ED presentations reported significantly increased ED presentations following intervention. Public educational interventions varied widely on type, duration, and content, with description of intervention development largely absent from studies, limiting the potential replication of successful interventions. Positive intervention effects were reported in the majority of studies; however, methodological weaknesses evident in a number of studies limited the generalizability of the observed effects. Reporting of specific intervention design was suboptimal and impeded the identification of key intervention components for reducing patient delay. The parallel delivery of public and professional interventions further limited the identification of successful intervention components. A lack of studies of sound methodological quality using, at a minimum, a controlled before and after design was identified in this review, and thus studies incorporating a rigorous study design are required to strengthen the evidence for public interventions to reduce patient delay in stroke. The potential clinical benefits of public interventions are far-reaching, and the challenge remains in translating knowledge improvements and correct behavioral intentions to appropriate behavior when stroke occurs.


MicroRNA expression distinguishes between germinal center B cell-like and activated B cell-like subtypes of diffuse large B cell lymphoma.
Diffuse large B cell lymphoma (DLBCL) is an aggressive malignancy that accounts for nearly 40% of all lymphoid tumors. This heterogeneous disease can be divided into germinal center B cell-like (GCB) and activated B cell-like (ABC) subtypes by gene expression and immunohistochemical profiling. Using microarray analysis on prototypic cell lines, we identified microRNAs (miR-155, miR-21 and miR-221) that were more highly expressed in ABC-type than GCB-type cell lines. These microRNAs were over-expressed in de novo DLBCL (n = 35), transformed DLBCL (n = 14) and follicular center lymphoma cases (n = 27) compared to normal B cells. Consistent with the cell line model, expression levels were higher in DLBCL cases with an ABC-type immunophenotype than those that were GCB-type (p < 0.05). Moreover, using multivariate analysis we found that expression of miR-21 was an independent prognostic indicator in de novo DLBCL (p < 0.05). Interestingly, expression levels of both miR-155 and miR-21 were also higher in nonmalignant ABC than in GCB cells. As we also demonstrate that expression of microRNAs can be measured reliably from routine paraffin-embedded biopsies of more than 8-years-old (p < 0.001), we suggest that microRNAs could be clinically useful molecular markers for DLBCL as well as other cancers.


Surface flaw detection using oblique angle illumination.
An analysis of a surface flaw detection method is presented in which oblique illumination is combined with a high pass spatial filter to detect the light scattered from surface flaws. The effects of surface finishes of test samples (meteoric plates) are assessed statistically, and the sensitivity of the system is calculated. Data have been collected on diffraction patterns and surface scratch detection for three stainless steel plates having different surface finishes. The results agree with theoretical considerations and are quite promising.


Threat and the Body: How the Heart Supports Fear Processing.
Mental processes depend upon a dynamic integration of brain and body. Emotions encompass internal physiological changes which, through interoception (sensing bodily states), underpin emotional feelings, for example, cardiovascular arousal can intensify feelings of fear and anxiety. The brain is informed about how quickly and strongly the heart is beating by signals from arterial baroreceptors. These fire in bursts after each heartbeat, and are quiet between heartbeats. The processing of fear stimuli is selectively enhanced by these phasic signals, and these inhibit the processing of other types of stimuli including physical pain. Behavioural and neuroimaging studies detail this differential impact of heart signals on the processing of salient stimuli, and add to knowledge linking rhythmic activity in brain and body to perceptual consciousness.


Adherence to a healthy diet according to the World Health Organization guidelines and all-cause mortality in elderly adults from Europe and the United States.
The World Health Organization (WHO) has formulated guidelines for a healthy diet to prevent chronic diseases and postpone death worldwide. Our objective was to investigate the association between the WHO guidelines, measured using the Healthy Diet Indicator (HDI), and all-cause mortality in elderly men and women from Europe and the United States. We analyzed data from 396,391 participants (42% women) in 11 prospective cohort studies who were 60 years of age or older at enrollment (in 1988-2005). HDI scores were based on 6 nutrients and 1 food group and ranged from 0 (least healthy diet) to 70 (healthiest diet). Adjusted cohort-specific hazard ratios were derived by using Cox proportional hazards regression and subsequently pooled using random-effects meta-analysis. During 4,497,957 person-years of follow-up, 84,978 deaths occurred. Median HDI scores ranged from 40 to 54 points across cohorts. For a 10-point increase in HDI score (representing adherence to an additional WHO guideline), the pooled adjusted hazard ratios were 0.90 (95% confidence interval (CI): 0.87, 0.93) for men and women combined, 0.89 (95% CI: 0.85, 0.92) for men, and 0.90 (95% CI: 0.85, 0.95) for women. These estimates translate to an increased life expectancy of 2 years at the age of 60 years. Greater adherence to the WHO guidelines is associated with greater longevity in elderly men and women in Europe and the United States.


TBHP-promoted sequential radical silylation and aromatisation of aryl isonitriles with silanes.
The tert-butyl hydroperoxide (TBHP) promoted sequential silylation and aromatisation of isonitriles was developed, where the silyl group was regioselectively installed at the 6-position of phenanthridines. This procedure tolerates a series of functional groups, such as fluoro, chloro, acetyl, methoxy carbonyl, cyano and trifluoromethyl. The addition of a silyl radical to the isonitrile followed by an intramolecular aromatic cyclization was involved in this transformation.


Multi-layer Scaffolds of Poly(caprolactone), Poly(glycerol sebacate) and Bioactive Glasses Manufactured by Combined 3D Printing and Electrospinning.
Three-dimensional (3D) printing has been combined with electrospinning to manufacture multi-layered polymer/glass scaffolds that possess multi-scale porosity, are mechanically robust, release bioactive compounds, degrade at a controlled rate and are biocompatible. Fibrous mats of poly (caprolactone) (PCL) and poly (glycerol sebacate) (PGS) have been directly electrospun on one side of 3D-printed grids of PCL-PGS blends containing bioactive glasses (BGs). The excellent adhesion between layers has resulted in composite scaffolds with a Young's modulus of 240-310 MPa, higher than that of 3D-printed grids (125-280 MPa, without the electrospun layer). The scaffolds degraded in vitro by releasing PGS and BGs, reaching a weight loss of ~14% after 56 days of incubation. Although the hydrolysis of PGS resulted in the acidification of the buffer medium (to a pH of 5.3-5.4), the release of alkaline ions from the BGs balanced that out and brought the pH back to 6.0. Cytotoxicity tests performed on fibroblasts showed that the PCL-PGS-BGs constructs were biocompatible, with cell viability of above 125% at day 2. This study demonstrates the fabrication of systems with engineered properties by the synergy of diverse technologies and materials (organic and inorganic) for potential applications in tendon and ligament tissue engineering.


Improving clinical trial design in psoriasis: Perspectives from the global dermatology community.
Clinical trials to test investigational drugs for the treatment of chronic plaque psoriasis currently lack standards for comparison of efficacy and safety data.The majority of studies do not address the important need for long-term treatment. The International Psoriasis Council (IPC) conducted two surveys of its members to assess the need for gold standards, active comparators, and long-term therapy in clinical trials. In Survey 1, 30 participants delivered viewpoints on active comparators for topical therapy (six questions), systemic therapy (nine questions), and continuous versus intermittent therapy (six questions). In Survey 2, 31 participants provided input on gold standards for treatment (five questions), appropriate comparators (four questions), and continuous versus intermittent therapy (six questions). The IPC leadership interpreted the results after each survey. The majority of participants (77% in Survey 1 and 89% in Survey 2) agreed that studies of investigative treatments should include an active comparator. Participants described the most important feature of a gold standard as a treatment that: is widely used and generally accepted (45%); has the best efficacy (42%); and is well tolerated (13%). The majority agreed that gold standards should be dependent on: patient subgroup; location/extent of psoriasis; and psoriasis subtype/morphology. It was also agreed that continuous therapy for more than 3 years is needed for patients with moderate-to-severe plaque psoriasis. We have provided an expert opinion regarding the definition of a gold standard in psoriasis and have also established that no single treatment can be the gold standard across all subgroups and types of the disease. A single gold standard for the treatment of psoriasis does not exist. The complexity and heterogeneity of psoriasis requires different gold standards for the various manifestations of psoriasis and for subgroups of patients reconciling comorbidities. Of note, 17 experts out of 30 selected methotrexate as the most nominated gold standard amongst systemic agents. The experts support the election of an active comparator as one that is most efficacious over just the best in a particular class. In concordance, 87% of respondents agreed that good tolerability is therefore not the lead criterion for selection of an active comparator in favor of effectiveness and broad use. Patients with moderate-to-severe plaque psoriasis require continuous therapy; this statement was supported by 93% of the experts. Reasons for considering long-term therapy included appearance of comorbidities, impairment of quality of life, possibility of relapse, and subjective complaints such as itch, pain, and joint disease.


Tackling poorly selected, collected, and reported outcomes in obstetrics and gynecology research.
Clinical research should ultimately improve patient care. To enable this, randomized controlled trials must select, collect, and report outcomes that are both relevant to clinical practice and genuinely reflect the perspectives of key stakeholders including health care professionals, researchers, and patients. Unfortunately, many randomized controlled trials fall short of this requirement. Complex issues, including a failure to take into account the perspectives of key stakeholders when selecting outcomes, variations in outcome definitions and measurement instruments, and outcome reporting bias make research evidence difficult to interpret, undermining the translation of research into clinical practice. Problems with poor outcome selection, measurement, and reporting can be addressed by developing, disseminating, and implementing core outcome sets. A core outcome set represents a minimum data set of outcomes developed using robust consensus science methods engaging diverse stakeholders including health care professionals, researchers, and patients. Core outcomes should be routinely utilized by researchers, collected in a standardized manner, and reported consistently in the final publication. They are currently being developed across our specialty including infertility, endometriosis, and preeclampsia. Recognizing poorly selected, collected, and reported outcomes as serious hindrances to progress in our specialty, more than 80 journals including the Journal, have come together to support the Core Outcomes in Women's and Newborn Health (CROWN) initiative. The consortium supports researchers to develop, disseminate, and implement core outcome sets. Implementing core outcome sets could make a profound contribution to addressing poorly selected, collected, and reported outcomes. Implementation should ensure future randomized controlled trials hold the necessary reach and relevance to inform clinical practice, enhance patient care, and improve patient outcomes.


Dangerous journey: documenting the experience of Tibetan refugees.
Since the 1950 invasion of Tibet by China, Tibetan refugees have attempted to flee into Nepal over the Himalayan mountains. We documented the experiences of a group of refugees making this journey. We conducted semistructured interviews with 50 recent refugees at the Tibetan Refugee Transit Centre in Kathmandu, Nepal. Participants ranged in age from 8 to 56 years, and 21 were female. The average length of their journey from Tibet to Nepal was 34 days. During their journey, a majority of the refugees encountered authorities or became involved in altercations with Nepali Maoist groups. Most of these interactions resulted in extortion and threats of expulsion. Several Tibetans were tortured, beaten with weapons, threatened with being shot, and robbed. Three women were sexually assaulted at gunpoint. The refugees who took part in this study experienced physical and mental hardships and, often, human rights abuses on their journey to Nepal. International pressure is needed to prevent human rights violations and reduce potential long-term physical and mental health effects associated with this dangerous crossing.


Characterization of Tunisian Bacillus thuringiensis strains with abundance of kurstaki subspecies harbouring insecticidal activities against the lepidopteran insect Ephestia kuehniella.
The study of 257 crystal-producing Bacillus thuringiensis isolates from bioinsecticide free soil samples collected from different sites in Tunisia, was performed by PCR amplification, using six primer pairs specific for cry1, cry2, cry3, cry4, and vip3A genes, by the investigation of strain plasmid pattern, crystal morphology and delta-endotoxin content and by the assessment of insecticidal activities against the lepidopteran insect Ephestia kuehniella. Based on plasmid pattern study, 11 representative strains of the different classes were subjected to morphological and molecular analyses. The comparison of the PFGE fingerprints confirmed the heterogeneity of these strains. B. thuringiensis kurstaki strains, harbouring at the same time the genes cry1A, cry2, cry1Ia, and vip3A, were the most abundant (65.4%). 33.34% of the new isolates showed particular delta-endotoxin profiles but no PCR products with the used primer sets. B. thuringiensis israelensis was shown to be also very rare among the Tunisian B. thuringiensis isolates diversity. These findings could have considerable impacts for the set up of new pest control biological agents.


Parathyroid hormone-like protein is a secretory product of atrial myocytes.
Parathyroid hormone-like protein (PLP) was originally identified from tumors associated with hypercalcemia. Recently, it has been found to be expressed in a stretch-responsive manner in several types of smooth muscle. We studied adult rat heart muscle for the presence of the PLP. Using immunohistology and the PCR, we demonstrated the presence of PLP and its mRNA in all heart chambers. Immunoelectron microscopy demonstrated PLP in secretory vesicles of atrial mycocytes. Using immunoassay, we demonstrated that atria contained a higher concentration of PLP than ventricles. Furthermore, primary cultures of both chambers released PLP into conditioned medium, with atria secreting more than ventricles. Considered with studies of the role of PLP in other tissues, our observations suggest that the production and secretion of PLP by cardiac myocytes represents a calcium-related regulatory function for this stretch-responsive polypeptide in the cardiovascular system. PLP in the heart may be the calcium counterpart for the atrial natriuretic-sodium regulatory axis of the cardiovascular system.


Reciprocal subsidies: dynamic interdependence between terrestrial and aquatic food webs.
Mutual trophic interactions between contiguous habitats have remained poorly understood despite their potential significance for community maintenance in ecological landscapes. In a deciduous forest and stream ecotone, aquatic insect emergence peaked around spring, when terrestrial invertebrate biomass was low. In contrast, terrestrial invertebrate input to the stream occurred primarily during summer, when aquatic invertebrate biomass was nearly at its lowest. Such reciprocal, across-habitat prey flux alternately subsidized both forest birds and stream fishes, accounting for 25.6% and 44.0% of the annual total energy budget of the bird and fish assemblages, respectively. Seasonal contrasts between allochthonous prey supply and in situ prey biomass determine the importance of reciprocal subsidies.


Improved social services and the burden of post-traumatic stress disorder among economically vulnerable people after a natural disaster: a modelling study.
Hurricanes and other natural disasters produce public health and economic consequences that last well beyond their immediate aftermath. Resource loss is a core driver of post-traumatic stress disorder (PTSD) after large-scale traumatic events. We examined the effect of restoration of residential and housing-related financial resources on recovery from PTSD in post-disaster contexts. We built an agent-based model, empiricised with observational and experimental data, to test the effects of differing health service approaches on PTSD recovery, measured by prevalence and persistence. We tested a social services case management (SSCM) approach similar to Psychological First Aid, featuring shelter-based social service provision and linkage to mental health treatment for people who were displaced and had income loss, by comparing the treatment effectiveness of usual care alone, usual care with SSCM, stepped care alone, and stepped care with SSCM. An SSCM approach to restore housing and provide linkage to mental health services among people who were displaced and had income loss after a large-scale natural disaster resulted in between 1·56 (95% CI 1·55-1·57) and 5·73 (5·04-6·91) times as many remitted PTSD cases as non-SSCM conditions at the end of the first year, and between 1·16 (1·16-1·17) and 2·28 (2·25-2·32) times as many remitted cases at the end of the second year. Restoring economic and housing resources to populations affected by a natural disaster would significantly reduce the mental health burden in populations, particularly those with resource loss, after a disaster. US Department of Health and Human Services.


Assessing Clinical Laboratory Quality: A College of American Pathologists Q-Probes Study of Prothrombin Time INR Structures, Processes, and Outcomes in 98 Laboratories.
The anticoagulant warfarin has been identified as the second most frequent drug responsible for serious, disabling, and fatal adverse drug events in the United States, and its effect on blood coagulation is monitored by the laboratory test called international normalized ratio (INR). To determine the presence of INR policies and procedures, INR practices, and completeness and timeliness of reporting critical INR results in participants' clinical laboratories. Participants reviewed their INR policies and procedure requirements, identified their practices by using a questionnaire, and studied completeness of documentation and timeliness of reporting critical value INR results for outpatients and emergency department patients. In 98 participating institutions, the 5 required policies and procedures were in place in 93% to 99% of clinical laboratories. Fifteen options for the allowable variations among duplicate results from different analyzers, 12 different timeliness goals for reporting critical values, and 18 unique critical value limits were used by participants. All required documentation elements were present in 94.8% of 192 reviewed INR validation reports. Critical value INR results were reported within the time frame established by the laboratory for 93.4% of 2604 results, but 1.0% of results were not reported. Although the median laboratories successfully communicated all critical results within their established time frames and had all the required validation elements based in their 2 most recent INR calculations, those participants at the lowest 10th percentile were successful in 80.0% and 85.7% of these requirements, respectively. Significant opportunities exist for adherence to INR procedural requirements and for practice patterns and timeliness goals for INR critical results' reporting.


3D Printing Bioactive PLGA Scaffolds Using DMSO as a Removable Solvent.
Present bioprinting techniques lack the methodology to print with bioactive materials that retain their biological functionalities. This constraint is due to the fact that extrusion-based printing of synthetic polymers is commonly performed at very high temperatures in order to achieve desired mechanical properties and printing resolutions. Consequently, current methodology prevents printing scaffolds embedded with bioactive molecules, such as growth factors. With the wide use of mesenchymal stem cells (MSCs) in regenerative medicine research, the integration of growth factors into 3D printed scaffolds is critical because it can allow for inducible MSC differentiation. We have successfully incorporated growth factors into extrusion printed poly (lactic-co-glycolic acid) (PLGA) scaffolds by introducing dimethyl sulfoxide (DMSO) for low temperature printing. Mechanical testing results demonstrated significantly different compressive and tensile properties for PLGA scaffold printed with or without DMSO. In particular, the PLGA-DMSO scaffold displayed a highly stretchable feature compared to the regular PLGA scaffold. The cellular response of growth factor introduction was evaluated in vitro using human mesenchymal stem cells (hMSCs). By evaporating the DMSO after printing, we ensured that there was no cytotoxic effect on seeded hMSCs. The addition of lineage specific growth factors led to increased expression of corresponding genetic markers for chondrogenesis, osteogenesis, and adipogenesis. We concluded that the use of DMSO for 3D printed scaffold fabrication with bioactive items is a revolutionary methodology in advancing regenerative medicine. The incorporation of bioactive molecules opens pathways to more therapeutic uses for 3D printing in treating damaged or deteriorating native tissue.


Excessive Daytime Sleepiness Independently Predicts Increased Cardiovascular Risk After Myocardial Infarction.
Excessive daytime sleepiness (EDS), a common symptom among patients with sleep-disordered breathing, is closely associated with the development of cardiovascular diseases, but its long-term prognostic value is not completely understood. The aim of this study was to investigate whether EDS would be an independent prognostic factor after myocardial infarction. We prospectively recruited 112 post-myocardial infarction patients. The Epworth Sleepiness Scale was completed before polysomnography, and EDS was defined as a score ≥11. After exclusion of 8 patients who accepted treatment with continuous positive airway pressure, 104 patients were followed up for 48 months. The primary composite end point was major adverse cardiac events. Patients with EDS had higher rates of major adverse cardiac events (48.4% versus 27.4%, χ2=5.27, P=0.022) and reinfarction (29.0% versus 5.5%, χ2=13.51, P=0.0002) compared with those without EDS. In the Cox proportional hazards model, patients with EDS had 2.15 times (95% confidence interval, 1.08-4.18; P=0.030) higher crude risk of major adverse cardiac events, with prognostic significance persisting after adjusting for age, diabetes mellitus, depression, left ventricular ejection fraction, apnea-hypopnea index, and nocturnal nadir oxygen saturation (hazard ratio: 2.13, 95% confidence interval, 1.04-4.26, P=0.039). Furthermore, among participants with moderate to severe sleep-disordered breathing, the presence of EDS was associated with higher risk of major adverse cardiac events than those without EDS, after adjusting for age and nadir oxygen saturation (hazard ratio: 3.17, 95% confidence interval, 1.22-7.76, P=0.019). EDS may be an independent prognostic factor of adverse outcome in post-myocardial infarction patients with moderate to severe sleep-disordered breathing. Evaluation of EDS may shed new light on risk stratification and identify treatment responders for this patient population.


Finasteride in the treatment of men with androgenetic alopecia. Finasteride Male Pattern Hair Loss Study Group.
Androgenetic alopecia (male pattern hair loss) is caused by androgen-dependent miniaturization of scalp hair follicles, with scalp dihydrotestosterone (DHT) implicated as a contributing cause. Finasteride, an inhibitor of type II 5alpha-reductase, decreases serum and scalp DHT by inhibiting conversion of testosterone to DHT. Our purpose was to determine whether finasteride treatment leads to clinical improvement in men with male pattern hair loss. In two 1-year trials, 1553 men (18 to 41 years of age) with male pattern hair loss received oral finasteride 1 mg/d or placebo, and 1215 men continued in blinded extension studies for a second year. Efficacy was evaluated by scalp hair counts, patient and investigator assessments, and review of photographs by an expert panel. Finasteride treatment improved scalp hair by all evaluation techniques at 1 and 2 years (P < .001 vs placebo, all comparisons). Clinically significant increases in hair count (baseline = 876 hairs), measured in a 1-inch diameter circular area (5.1 cm2) of balding vertex scalp, were observed with finasteride treatment (107 and 138 hairs vs placebo at 1 and 2 years, respectively; P < .001). Treatment with placebo resulted in progressive hair loss. Patients' self-assessment demonstrated that finasteride treatment slowed hair loss, increased hair growth, and improved appearance of hair. These improvements were corroborated by investigator assessments and assessments of photographs. Adverse effects were minimal. In men with male pattern hair loss, finasteride 1 mg/d slowed the progression of hair loss and increased hair growth in clinical trials over 2 years.


Human MIEF1 recruits Drp1 to mitochondrial outer membranes and promotes mitochondrial fusion rather than fission.
Mitochondrial morphology is controlled by two opposing processes: fusion and fission. Drp1 (dynamin-related protein 1) and hFis1 are two key players of mitochondrial fission, but how Drp1 is recruited to mitochondria and how Drp1-mediated mitochondrial fission is regulated in mammals is poorly understood. Here, we identify the vertebrate-specific protein MIEF1 (mitochondrial elongation factor 1; independently identified as MiD51), which is anchored to the outer mitochondrial membrane. Elevated MIEF1 levels induce extensive mitochondrial fusion, whereas depletion of MIEF1 causes mitochondrial fragmentation. MIEF1 interacts with and recruits Drp1 to mitochondria in a manner independent of hFis1, Mff (mitochondrial fission factor) and Mfn2 (mitofusin 2), but inhibits Drp1 activity, thus executing a negative effect on mitochondrial fission. MIEF1 also interacts with hFis1 and elevated hFis1 levels partially reverse the MIEF1-induced fusion phenotype. In addition to inhibiting Drp1, MIEF1 also actively promotes fusion, but in a manner distinct from mitofusins. In conclusion, our findings uncover a novel mechanism which controls the mitochondrial fusion-fission machinery in vertebrates. As MIEF1 is vertebrate-specific, these data also reveal important differences between yeast and vertebrates in the regulation of mitochondrial dynamics.


Development of a humanized C1q A chain knock-in mouse: assessment of antibody independent beta-amyloid induced complement activation.
Evidence has been accumulating for a role of inflammation in the development of Alzheimer's disease (AD), a progressive neurodegenerative disorder causing a common form of dementia in the elderly. C1q, part of the initiation component of the classical complement pathway (CCP), is associated with beta-sheet, fibrillar amyloid plaques in AD brain. In vitro, beta-amyloid peptide in fibrillar beta-sheet conformation (fAbeta) can activate CCP via interaction of specific negatively charged amino acids of the beta-amyloid fibril with human C1q. Previous results using peptide inhibitors led to the hypothesis that a highly positively charged domain consisting of three arginine residues, such as that present in the N-terminal collagen-like region of the human C1q A chain, may be critical for the activation event. However, mouse C1q A chain lacks two of the three arginines in the corresponding C1q A chain collagen-like region. To test the hypothesis that this divergent activation domain results in a weaker C' activation and thus may contribute to the lower neuronal loss observed in transgenic mouse models of AD, a partially humanized C1q A chain knock-in mouse was generated. The mouse C1q A chain gene was modified by homologous recombination to replace 4 residues in the 13-20 amino acid region to mimic the corresponding sequence from human A chain. No significant differences in the expression of C1q were found in sera from mice homozygous for the humanized C1q A chain compared to littermate wild type mice. Two distinct C1 activation assays demonstrated that activation by fAbeta was not significantly different in the homozygous humanized C1q A chain mice. Activation of C1 by DNA, previously hypothesized to interact with this C1q A chain arginine-rich sequence was also not significantly different in the knock-in mouse. Molecular modeling based on the published crystal structure of human C1q B chain globular head and a beta-sheet model for fibrillar amyloid suggests an alternative arginine ladder in the globular head domain may provide the functional C1 activating interaction domains. The humanized C1q mouse generated here should provide a better animal model for assessing the mechanisms of C1 activation and the contribution of C1q to human health and disease.


Model for the orientational ordering of the plant microtubule cortical array.
The plant microtubule cortical array is a striking feature of all growing plant cells. It consists of a more or less homogeneously distributed array of highly aligned microtubules connected to the inner side of the plasma membrane and oriented transversely to the cell growth axis. Here, we formulate a continuum model to describe the origin of orientational order in such confined arrays of dynamical microtubules. The model is based on recent experimental observations that show that a growing cortical microtubule can interact through angle dependent collisions with pre-existing microtubules that can lead either to co-alignment of the growth, retraction through catastrophe induction or crossing over the encountered microtubule. We identify a single control parameter, which is fully determined by the nucleation rate and intrinsic dynamics of individual microtubules. We solve the model analytically in the stationary isotropic phase, discuss the limits of stability of this isotropic phase, and explicitly solve for the ordered stationary states in a simplified version of the model.


Paclitaxel-coated balloon versus drug-eluting stent during PCI of small coronary vessels, a prospective randomised clinical trial. The PICCOLETO study.
Percutaneous coronary intervention (PCI) of small vessels is limited by an increased risk of restenosis and adverse outcome, even when drug-eluting stents (DES) are employed. In recent years, the paclitaxel-coated balloon (PCB) has been shown to reduce neointimal proliferation and the need for target lesion revascularization (TLR) in an in-stent restenosis setting. The impact of a PCB during PCI of small coronary vessels was evaluated and compared to one of the most widely used DES. In the PICCOLETO randomised clinical trial, patients with stable or unstable angina undergoing PCI of small coronary vessels (< or = 2.75 mm) were randomised to Dior PCB (28 patients) or Taxus DES (29 patients). The primary study end point was per cent diameter stenosis at 6-month angiographic follow-up (non-inferiority), secondary end points were angiographic binary restenosis and occurrence of major adverse cardiac events (MACE: death, Q-wave myocardial infarction, TLR) at 9 month follow-up. The two groups were not dissimilar regarding clinical and angiographic characteristics. Study was interrupted after enrolment of two-thirds of patients due to a clear superiority of one study group. The primary end point was not met, because the PCB group showed higher per cent diameter stenosis (43.6% vs 24.3%, p=0.029); angiographic restenosis was higher as well (32.1 vs 10.3%, p=0.043), whereas MACE were 35.7% in the PCB group and 13.8% in the DES group (p=0.054). Dior PCB failed to show equivalence to Taxus DES regarding angiographic end points during PCI of small coronary arteries. CLINICAL TRIAL REGISTRATION NUMBER (EUDRACT CODE): 2009-012268-15.


Contribution of uncertainty in estimation of active drag using assisted towing method in front crawl swimming.
Active drag force in swimming can be calculated from a function of five different variables: swim velocity, tow velocity, belt force, power output and exponent of velocity. The accuracy of the drag force value is dependent on the accuracy of each variable, and on the contribution of each variable to drag estimation. To calculate uncertainty in drag value, first the derivatives of the active drag equation with respect to each variable were obtained. Second, these were multiplied by the uncertainty of that variable. Twelve national age and open level swimmers were recruited to complete four free swimming and five active drag trials. The uncertainties for the free and the tow swim velocities, and for the belt force, contributed approximately 5-6% and 2-3% error, respectively, in calculation of drag. The result of the uncertainty of the velocity exponent (1.8-2.6) indicated a contribution of about 6% error in active drag. The contribution of unequal power output showed that if a power changed 7.5% between conditions, it would lead to about 30% error in calculated drag. Consequently, if a swimmer did not maintain constant power output between conditions, there would be substantial errors in the calculation of active drag.


"Below the Line": The tobacco industry and youth smoking.
This paper provides a comprehensive account of how the tobacco industry, over time, has promoted its products to young people. A comprehensive search of tobacco industry documents relating to youth smoking was conducted using documents available on the World Wide Web through the Master Settlement Agreement. The documents provide evidence that the industry invested great time and resources in developing strategies to attract young people through Youth Smoking Prevention strategies (including education strategies) and marketing to youth. The results include information from published literature and direct excerpts from the tobacco industry documents. The tobacco industry documents confirm that the tobacco industry has promoted and supported strategies that are ineffective in reducing smoking by youth, and opposed strategies that have proven to be effective. It is clear from the documents reviewed that the industry values the youth market and through a number of measures continues to promote its products to young people.


Green tea (-)-epigallocatechin gallate inhibits insulin stimulation of 3T3-L1 preadipocyte mitogenesis via the 67-kDa laminin receptor pathway.
Insulin and (-)-epigallocatechin gallate (EGCG) have been reported to regulate fat cell mitogenesis and adipogenesis, respectively. This study investigated the pathways involved in EGCG modulation of insulin-stimulated mitogenesis in 3T3-L1 preadipocytes. EGCG inhibited insulin stimulation of preadipocyte proliferation in a dose- and time-dependent manner. EGCG also suppressed insulin-stimulated phosphorylation of the insulin receptor-beta, insulin receptor (IR) substrates 1 and 2 (IRS1 and IRS2), and mitogen-activated protein kinase pathway proteins, RAF1, MEK1/2, and ERK1/2, but not JNK. Furthermore, EGCG inhibited the association of IR with the IRS1 and IRS2 proteins, but not with the IRS4 protein. These data suggest that EGCG selectively affects particular types of IRS and MAPK family members. Generally, EGCG was more effective than epicatechin, epicatechin gallate, and epigallocatechin in modulating insulin-stimulated mitogenic signaling. We identified the EGCG receptor [also known as the 67-kDa laminin receptor (67LR)] in fat cells and found that its expression was sensitive to growth phase, tissue type, and differentiation state. Pretreatment of preadipocytes with 67LR antiserum prevented the effects of EGCG on insulin-stimulated phosphorylation of IRS2, RAF1, and ERK1/2 and insulin-stimulated preadipocyte proliferation (cell number and bromodeoxyuridine incorporation). Moreover, EGCG tended to increase insulin-stimulated associations between the 67LR and IR, IRS1, IRS2, and IRS4 proteins. These data suggest that EGCG mediates anti-insulin signaling in preadipocyte mitogenesis via the 67LR pathway.


NS35 and not vp7 is the soluble rotavirus protein which binds to target cells.
Recent studies using radiolabeled rotavirus lysates have demonstrated a 35-kilodalton viral protein that binds specifically to the surface of MA104 cells (N. Fukuhara, O. Yoshie, S. Kitakoa, and T. Konno, J. Virol. 62:2209-2218, 1988; M. Sabara, J. Gilchrist, G.R. Hudson, and L.A. Babiuk, J. Virol. 53:58-66, 1985). The binding protein was identified as vp7, an outer capsid glycoprotein and the product of rotavirus gene 9. These studies concluded that vp7 mediated viral attachment to MA104 cells and that the binding of a soluble viral protein to a cell monolayer mirrored the attachment of infectious rotavirus to permissive tissue culture cells. In the process of determining which viral protein adheres to the in vivo target cell in rotavirus infection, the mammalian enterocyte, we found that a similar 35-kilodalton rhesus rotavirus (RRV) protein bound to both MA104 cells and murine enterocytes. However, further analysis of this protein by immunoprecipitation, inhibition of glycosylation, and partial proteolysis showed that it was not the RRV gene 9 product, vp7, but the gene 8 product, NS35. Similar results were obtained by using porcine rotavirus (OSU) and bovine rotavirus (NCDV) strains. Binding studies using the in vitro-expressed products of RRV genes 8 and 9 confirmed these results. Since double-shelled virions inhibited the binding of NS35 to cells, we looked for the presence of this protein in preparations of purified virus. Examination of density gradient-purified virus preparations revealed biochemical and immunological evidence that NS35 copurifies in small amounts with double-shelled virions. Thus, these studies clearly demonstrated that when rotavirus proteins are prepared in a soluble form from infected cells, NS35, and not vp7, binds to the surfaces of MA104 cells and murine enterocytes. The observations do not confirm previous experimental results which supported the hypothesis that vp7 was the viral attachment protein. They are consistent with but do not prove the hypothesis that NS35 functions as the rotavirus attachment protein.


Decisive situations affecting partners' support to continuous positive airway pressure-treated patients with obstructive sleep apnea syndrome: a critical incident technique analysis of the initial treatment phase.
Effective treatment of obstructive sleep apnea syndrome (OSAS) with continuous positive airway pressure (CPAP) can reduce morbidity and mortality, but adherence rates are low. The partner has an important role in supporting the patient, but this role may be adversely affected by difficulties during the early phase of the CPAP initiation. The aim of this study was to explore and describe decisive situations affecting partners' support to patients with OSAS and how the partners manage these situations during the initial phase of CPAP treatment. A qualitative descriptive design using critical incident technique was used. A total of 542 decisive situations affecting partners' support and 222 situations describing managing were collected by means of interviews with 25 strategically selected partners of patients with CPAP treated OSAS. Adverse effects, limited effect, practical and psychosocial problems, limited presence, and inappropriate initiation emerged as negative influences on the partners' support. A well-functioning treatment, improvements, high motivation, and receiving support from others were identified as positive influences on the partners' support. The partner managed the situations by letting the patient handle the CPAP treatment by himself/herself, by handling the treatment together with the patient, or taking over the handling of CPAP treatment. Increased knowledge about the different situations that affect the partners' support negatively or positively and how these situations are managed by partners can be used in educational situations involving both patients and partners during CPAP initiation.


The effects of in vitro ageing on the exopeptidases of human diploid fibroblasts.
Six exopeptidases present in human diploid fibroblasts were identified by separation on polyacrylamide gel electrophoresis and their activity profiles against 17 dipeptides, two tripeptides and L-leucine-p-nitroanilide determined. No differences in relative activity or in the electrophoretic patterns of any of the six exopeptidases were detected with ageing. Aminoacylarylamidase activity assayed spectrophotometrically showed significantly increased activity in the middle age-group cells as opposed to the enzyme isolated from young and old cells. Heat-inactivation studies using the same substrate suggested the possibility of an increased proportion of heat-labile enzyme in the old cells but interpretation of the data was difficult because of the complex nature of the inactivation curves obtained. Overall, the results tended to refute the hypothesis that age-related changes in the free amino acid pool of human diploid fibroblasts were associated with significant alterations in the activities of cellular exopeptidases.


Rotational acetabular osteotomy for osteonecrosis with collapse of the femoral head in young patients.
While rotational acetabular osteotomy has been reported to be successful for the treatment of osteoarthritis of the dysplastic hip, little is known about its efficacy in the treatment of osteonecrosis of the femoral head. We retrospectively reviewed the results for a consecutive series of twenty-one patients (twenty-five hips) who had undergone rotational acetabular osteotomy between 1995 and 2001 for the treatment of extensive osteonecrosis of the femoral head associated with collapse. All but two of the patients had a history of steroid therapy as part of a treatment regimen for various diseases. At the time of surgery, the mean age of the five men and sixteen women was 29.0 years. The mean duration of follow-up was forty-nine months. No patient was lost to follow-up. The lesions were classified according to the staging system described by Steinberg et al., and the extent of necrosis was measured with use of the criteria described by Kerboul et al. Clinical evaluation was performed with use of the scoring system of Merle d'Aubigne and Postel. Radiographic evaluation was performed with use of yearly serial anteroposterior and lateral plain radiographs. The mean Merle d'Aubigne and Postel score improved from 11.3 points preoperatively to 14.9 points at the time of the final follow-up (p < 0.001). The mean pain score improved from 3.0 to 5.6 points (p < 0.001). However, the mean mobility score was 5.3 points preoperatively but only 4.9 points postoperatively (p = 0.1). All of the osteotomy sites showed radiographic evidence of osseous union at the time of the latest follow-up. Collapse of the femoral head progressed in seven hips, but in six of these hips the change in the extent of collapse was <2 mm. In the present study of young patients with extensive osteonecrosis and collapse of the femoral head, rotational acetabular osteotomy was associated with symptomatic relief and absence of substantial collapse of the femoral head at the time of early to intermediate-term follow-up.


Arabidopsis thaliana transcription factors bZIP19 and bZIP23 regulate the adaptation to zinc deficiency.
Zinc is an essential micronutrient for all living organisms. When facing a shortage in zinc supply, plants adapt by enhancing the zinc uptake capacity. The molecular regulators controlling this adaptation are not known. We present the identification of two closely related members of the Arabidopsis thaliana basic-region leucine-zipper (bZIP) transcription factor gene family, bZIP19 and bZIP23, that regulate the adaptation to low zinc supply. They were identified, in a yeast-one-hybrid screening, to associate to promoter regions of the zinc deficiency-induced ZIP4 gene of the Zrt- and Irt-related protein (ZIP) family of metal transporters. Although mutation of only one of the bZIP genes hardly affects plants, we show that the bzip19 bzip23 double mutant is hypersensitive to zinc deficiency. Unlike the wild type, the bzip19 bzip23 mutant is unable to induce the expression of a small set of genes that constitutes the primary response to zinc deficiency, comprising additional ZIP metal transporter genes. This set of target genes is characterized by the presence of one or more copies of a 10-bp imperfect palindrome in their promoter region, to which both bZIP proteins can bind. The bZIP19 and bZIP23 transcription factors, their target genes, and the characteristic cis zinc deficiency response elements they can bind to are conserved in higher plants. These findings are a significant step forward to unravel the molecular mechanism of zinc homeostasis in plants, allowing the improvement of zinc bio-fortification to alleviate human nutrition problems and phytoremediation strategies to clean contaminated soils.


Accuracy of CT Angiography for Differentiating Pseudo-Occlusion from True Occlusion or High-Grade Stenosis of the Extracranial ICA in Acute Ischemic Stroke: A Retrospective MR CLEAN Substudy.
The absence of opacification on CTA in the extracranial ICA in acute ischemic stroke may be caused by atherosclerotic occlusion, dissection, or pseudo-occlusion. The latter is explained by sluggish or stagnant flow in a patent artery caused by a distal intracranial occlusion. This study aimed to explore the accuracy of CTA for differentiating pseudo-occlusion from true occlusion of the extracranial ICA. All patients from the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) with an apparent ICA occlusion on CTA and available DSA images were included. Two independent observers classified CTA images as atherosclerotic cause (occlusion/high-grade stenosis), dissection, or suspected pseudo-occlusion. Pseudo-occlusion was suspected if CTA showed a gradual contrast decline located above the level of the carotid bulb, especially in the presence of an occluded intracranial ICA bifurcation (T-occlusion). DSA images, classified into the same 3 categories, were used as the criterion standard. In 108 of 476 patients (23%), CTA showed an apparent extracranial carotid occlusion. DSA was available in 46 of these, showing an atherosclerotic cause in 13 (28%), dissection in 16 (35%), and pseudo-occlusion in 17 (37%). The sensitivity for detecting pseudo-occlusion on CTA was 82% (95% CI, 57-96) for both observers; specificity was 76% (95% CI, 56-90) and 86% (95% CI, 68-96) for observers 1 and 2, respectively. The κ value for interobserver agreement was .77, indicating substantial agreement. T-occlusions were more frequent in pseudo- than true occlusions (82% versus 21%, P < .001). On CTA, extracranial ICA pseudo-occlusions can be differentiated from true carotid occlusions.


Direct observation of aminyl radical intermediate during single-crystal to single-crystal photoinduced Orton rearrangement.
A photoinduced analogue of the thermal Orton rearrangement reaction by which an N-chlorine atom from a side amino group is transferred to a phenyl ring was studied in the solid state. Contrary to the mixture of products obtained in solution, in the N-chloro-N-acetylaminobenzene crystals the photoreaction proceeds with complete preservation of crystallinity, affording selectively and quantitatively the para isomer of chloroacetanilide. Study of the reaction mechanism by in situ steady-state photodiffraction, a combination of photoexcitation by UV light and single-crystal X-ray diffraction analysis, provided evidence for creation of N-acetyl-N-phenylaminyl (AcPhN*) radical as a metastable reaction intermediate. The structure of the aminyl radical produced in 9.2% yield from the major disordered component in the statically 85.6:14.4 disordered crystal was directly observed for the first time. The unprecedented stability of the radical is prescribed to the solid-state cage effect, the reactive center of the radical species being locked away from the reactive target molecules. The creation of the radical and its head-to-tail chain reaction within the undulated hydrogen-bonded ribbons involving the acetyl carbonyl group are employed to explain the high selectivity of the photoinduced single-crystal to single-crystal Orton rearrangement. On the basis of the change of the crystal structure and the physicochemical data, a three-center five-atom mechanism involving homolytic cleavage of the N-Cl bond followed by hydrogen abstraction by the carbonyl group is suggested for the solid-state photoinduced Orton rearrangement.


Prescription of Long-Acting Opioids and Mortality in Patients With Chronic Noncancer Pain.
Long-acting opioids increase the risk of unintentional overdose deaths but also may increase mortality from cardiorespiratory and other causes. To compare all-cause mortality for patients with chronic noncancer pain who were prescribed either long-acting opioids or alternative medications for moderate to severe chronic pain. Retrospective cohort study between 1999 and 2012 of Tennessee Medicaid patients with chronic noncancer pain and no evidence of palliative or end-of-life care. Propensity score-matched new episodes of prescribed therapy for long-acting opioids or either analgesic anticonvulsants or low-dose cyclic antidepressants (control medications). Total and cause-specific mortality as determined from death certificates. Adjusted hazard ratios (HRs) and risk differences (difference in incidence of death) were calculated for long-acting opioid therapy vs control medication. There were 22,912 new episodes of prescribed therapy for both long-acting opioids and control medications (mean [SD] age, 48 [11] years; 60% women). The long-acting opioid group was followed up for a mean 176 days and had 185 deaths and the control treatment group was followed up for a mean 128 days and had 87 deaths. The HR for total mortality was 1.64 (95% CI, 1.26-2.12) with a risk difference of 68.5 excess deaths (95% CI, 28.2-120.7) per 10,000 person-years. Increased risk was due to out-of-hospital deaths (154 long-acting opioid, 60 control deaths; HR, 1.90; 95% CI, 1.40-2.58; risk difference, 67.1; 95% CI, 30.1-117.3) excess deaths per 10,000 person-years. For out-of-hospital deaths other than unintentional overdose (120 long-acting opioid, 53 control deaths), the HR was 1.72 (95% CI, 1.24-2.39) with a risk difference of 47.4 excess deaths (95% CI, 15.7-91.4) per 10,000 person-years. The HR for cardiovascular deaths (79 long-acting opioid, 36 control deaths) was 1.65 (95% CI, 1.10-2.46) with a risk difference of 28.9 excess deaths (95% CI, 4.6-65.3) per 10,000 person-years. The HR during the first 30 days of therapy (53 long-acting opioid, 13 control deaths) was 4.16 (95% CI, 2.27-7.63) with a risk difference of 200 excess deaths (95% CI, 80-420) per 10,000 person-years. Prescription of long-acting opioids for chronic noncancer pain, compared with anticonvulsants or cyclic antidepressants, was associated with a significantly increased risk of all-cause mortality, including deaths from causes other than overdose, with a modest absolute risk difference. These findings should be considered when evaluating harms and benefits of treatment.


Multiple small "imaging" branch-duct type intraductal papillary mucinous neoplasms (IPMNs) in familial pancreatic cancer: indicator for concomitant high grade pancreatic intraepithelial neoplasia?
Most screening programs for familial pancreatic cancer are currently based on endoscopic ultrasonography and/or magnetic resonance imaging (MRI). Cystic lesions, especially those suspicious for small intraductal pancreatic mucinous neoplasms (IPMNs) of the branch ducts, can be visualized in up to 40 % of individuals at risk, but their pathological importance in the setting of FPC is yet not well established. Individuals at risk from a prospective screening program for familial pancreatic cancer with small "imaging" IPMNs of the branch-duct type (BD-IPMN) who underwent pancreatic resection were analysed regarding clinico-pathological data and the locations of pancreatic lesions. Five of 125 individuals at risk who underwent screening had multiple small (size 2-10 mm) unicystic lesions and/or multicystic single lesions in the pancreatic body and tail suspicious for BD-IPMNs upon MRI imaging and decided to undergo surgical resection after interdisciplinary counselling, although none fulfilled the consensus criteria for IPMN resection. Histological examination revealed BD-IPMNs with low or moderate dysplasia of the gastric type in combination with multifocal PanIN2 and PanIN3 lesions in 4 individuals. The remaining patient had only tiny ductectasias in the pancreatic tail with multifocal PanIN 2 lesions in the entire gland and one PanIN3 lesion in the pancreatic head. Intriguingly, the location of the most dysplastic histological lesions (PanIN3) did not correspond to the preoperatively detected lesions and were not visible in preoperative imaging. In the setting of FPC, the presence of multiple small "imaging" BD-IPMNs may indicate the presence of high-grade PanIN lesions elsewhere in the pancreas.


Long-term function after pseudo-pollicization of the little finger.
This article presents a technique for facilitating use of pinch between the ring and little fingers for use in rare cases of congenital absence, or severe hypoplasia, of the thumb in which pollicization of the index finger is impossible, or not advised because the child is already pinching by scissor action between the ring and little fingers. The technique avoids drawing attention to the hand, as is the case after true pollicization of the little finger. The technique was used in five hands in five children. Three of the patients could only be followed for under 2 years. Two patients were available for longer follow-up of 6 years and 2 months and 3 years after surgery. The surgery was shown to facilitate opening of the web and pinch between the little and ring finger tips, and continues to be of functional value to the children as they grow.


Inhibition of platelet aggregation by carbon monoxide is mediated by activation of guanylate cyclase.
Carbon monoxide (CO) inhibits human platelet aggregation triggered with threshold levels of agonists like arachidonate, ADP, collagen, thrombin, or the prostaglandin endoperoxide analogue U46619. This inhibition is counteracted by illumination with light above 400 nm indicating the involvement of a ferrous hemoprotein. An earlier suggestion that the mechanism of CO inhibition involves the cytochrome P450 protein thromboxane A2 synthase was ruled out as well as the involvement of the iron containing enzymes like cyclooxygenase or 12-lipoxygenase. In the presence of CO, no arachidonate was released from phospholipids, no increase of intracellular calcium levels was observed, and phospholipase C was not activated suggesting that the transducing mechanisms from the receptors to phospholipase C was effected in the presence of CO. cAMP levels were also unchanged but cGMP levels showed an increase of about 30%. By comparison with the guanylate cyclase stimulator nitroprusside, it was shown that such levels could block aggregation. In a 10,000 X g supernatant, CO enhanced guanylate cyclase activity 4-fold, supporting the view that CO acts by increasing platelet cGMP levels. With respect to the mechanism of guanylate cyclase action, the binding of CO to the regulatory subunit of guanylate cyclase must be responsible for the observed activation. It is concluded that cGMP is an important feedback regulator of the Pl response and that already a 25% increase in its steady state levels can cause inhibition of platelet aggregation.


Brigatinib versus Crizotinib in ALK-Positive Non-Small-Cell Lung Cancer.
Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, has robust efficacy in patients with ALK-positive non-small-cell lung cancer (NSCLC) that is refractory to crizotinib. The efficacy of brigatinib, as compared with crizotinib, in patients with advanced ALK-positive NSCLC who have not previously received an ALK inhibitor is unclear. In an open-label, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with advanced ALK-positive NSCLC who had not previously received ALK inhibitors to receive brigatinib at a dose of 180 mg once daily (with a 7-day lead-in period at 90 mg) or crizotinib at a dose of 250 mg twice daily. The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included the objective response rate and intracranial response. The first interim analysis was planned when approximately 50% of 198 expected events of disease progression or death had occurred. A total of 275 patients underwent randomization; 137 were assigned to brigatinib and 138 to crizotinib. At the first interim analysis (99 events), the median follow-up was 11.0 months in the brigatinib group and 9.3 months in the crizotinib group. The rate of progression-free survival was higher with brigatinib than with crizotinib (estimated 12-month progression-free survival, 67% [95% confidence interval {CI}, 56 to 75] vs. 43% [95% CI, 32 to 53]; hazard ratio for disease progression or death, 0.49 [95% CI, 0.33 to 0.74]; P<0.001 by the log-rank test). The confirmed objective response rate was 71% (95% CI, 62 to 78) with brigatinib and 60% (95% CI, 51 to 68) with crizotinib; the confirmed rate of intracranial response among patients with measurable lesions was 78% (95% CI, 52 to 94) and 29% (95% CI, 11 to 52), respectively. No new safety concerns were noted. Among patients with ALK-positive NSCLC who had not previously received an ALK inhibitor, progression-free survival was significantly longer among patients who received brigatinib than among those who received crizotinib. (Funded by Ariad Pharmaceuticals; ALTA-1L ClinicalTrials.gov number, NCT02737501 .).


Towards a greater understanding of the illicit tobacco trade in Europe: a review of the PMI funded 'Project Star' report.
Following a legal agreement with the European Union (EU), Philip Morris International (PMI) commissions a yearly report ('Project Star', PS) on the European illicit cigarette trade from KPMG, the global accountancy firm. Review of PS 2010 report. Comparison with data from independent sources including a 2010 pan-European survey (N=18,056). Within PS, data covering all 27 EU countries are entered into a model. While the model itself seems appropriate, concerns are identified with the methodologies underlying the data inputs and thus their quality: there is little transparency over methodologies; interview data underestimate legal non-domestic product partly by failing to account for legal cross-border sales; illicit cigarette estimates rely on tobacco industry empty pack surveys which may overestimate illicit; and there is an over-reliance on data supplied by PMI with inadequate external validation. Thus, PMI sales data are validated using PMI smoking prevalence estimates, yet PMI is unable to provide sales (shipment) data for the Greek islands and its prevalence estimates differ grossly from independent data. Consequently, comparisons with independent data suggest PS will tend to overestimate illicit cigarette levels particularly where cross-border shopping is frequent (Austria, Finland, France) and in Western compared with Eastern European countries. The model also provides data on the nature of the illicit cigarette market independent of seizure data suggesting that almost a quarter of the illicit cigarette market in 2010 comprised PMI's own brands compared with just 5% counterfeited PMI brands; a finding hidden in PMI's public representation of the data. PS overestimates illicit cigarette levels in some European countries and suggests PMI's supply chain control is inadequate. Its publication serves the interests of PMI over those of the EU and its member states. PS requires greater transparency, external scrutiny and use of independent data.


Pregabalin Attenuates Carrageenan-Induced Acute Inflammation in Rats by Inhibiting Proinflammatory Cytokine Levels.
Pregabalin (PGB) is a compound used in the treatment of epilepsy, anxiety, and neuropathic pain. Experimental data also indicate that PGB can reduce inflammatory pain. We aimed to investigate the anti-inflammatory effects of PGB on carrageenan (CAR)-induced paw edema and its effects on tumor necrosis factor-α (TNF-α) and interleukine-1β (IL-1β) acting as acute phase cytokines in inflammation, and anti-inflammatory cytokine IL-10, in rats. Single doses of PGB 30, 50, and 100 mg/kg and indomethacin (INDO) 5 mg/kg in the treatment groups and saline in the control group were injected once intraperitoneally prior to administration of 100 μl of 1% CAR into the right hind paw of the rats. The paw thickness was measured using gauge calipers (Vernier calipers) before (0 hour) and every hour afterwards for 6 hours following the inflammation induction. The cytokine levels in the blood serum obtained intracardiacally were determined after 6 hours using the enzyme-linked immunosorbent assay method. p<0.05 was considered statistically significant. There was no significant difference between the 0 and 6th hour considering the paw thickness in all groups, except in the CAR group. CAR significantly increased the paw thickness at 6 hours compared to the 0 hour. All doses of PGB and INDO significantly reduced the paw thickness after 6 hours compared to the CAR group. The TNF-α and IL-1β levels in the PGB and INDO groups were comparable to the control group, whereas in the CAR group, these levels were increased. The IL-10 level was enhanced in the PGB 50 mg/kg and INDO groups. It was observed that all doses of PGB exerted anti-inflammatory-like effects comparable to INDO, supported by their effects on the levels of cytokines.


Construction of a patterned hydrogel-fibrous mat bilayer structure to mimic choroid and Bruch's membrane layers of retina.
Deterioration of retina and death of the retinal cells due to age, diabetes, or occlusion can cause retinal degeneration which leads to loss of vision. In this study, it is aimed to design a bilayered matrix to mimic the choroid and the Bruch's membrane of the retinal tissue. As choroid, a microchanneled network resembling a fractal tree design was fabricated by photolithography over photo-cross-linkable methacrylated hyaluronic acid hydrogel. Gelatin or collagen was immobilized into the microchannels to enhance adherence of Human Umbilical Vein Endothelial Cells (HUVEC). At late culture periods (2 weeks), formation of tubular structures due to proliferation of the attached cells was observed. As Bruch's membrane, an electrospun fibroin nanofiber mat was produced to grow retinal pigment epithelium (RPE) cells on. Cellular interactions between RPE and HUVEC in the microchannels were investigated in a coculture model in a noncontact mode. It was deduced that by combining the RPE layer on the highly permeable Bruch's membrane with the choroid layer populated by HUVECs, a retinal substitute which might have a potential for use in the treatment of retinal diseases is possible. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2166-2177, 2016.


Physical Activity, Fatigue, and Sleep in People with Parkinson's Disease: A Secondary per Protocol Analysis from an Intervention Trial.
Symptoms of Parkinson's can result in low physical activity and poor sleep patterns which can have a detrimental effect on a person's quality of life. To date, studies looking into exercise interventions for people with Parkinson's (PwP) for symptom management are promising but inconclusive. The aim of this study is to estimate the effect of a clearly defined exercise prescription on general physical activity levels, fatigue, sleep, and quality of life in PwP. Method. PwP randomised into either an exercise group (29; 16 males, 13 females; mean age 67 years (7.12)) or a control handwriting group (36; 19 males; 17 females; mean age 67 years (5.88)) as part of a larger trial were included in this substudy if they had completed a 6-month weekly exercise programme (intervention group) and had complete objective physical activity data (intervention and control group). Sleep and fatigue were recorded from self-reported measures, and physical activity levels measured through the use of accelerometers worn 24 hours/day over a seven-day testing period at baseline and following the 24-week intervention. A Wilcoxon's test followed by a Mann-Whitney post hoc analysis was used, and effect sizes were calculated. Results. Participants showed a significant increase in time spent in sedentary and light activities during the overnight period postintervention in both exercise and handwriting groups (p < 0.05) with a moderate effect found for the change in sedentary and light activities in the overnight hours for both groups, over time (0.32 and 0.37-0.38, resp.). There was no impact on self-reported fatigue or sleep. Conclusion. The observed moderate effect on sedentary and light activities overnight could suggest an objective improvement in sleep patterns for individuals participating in both exercise and handwriting interventions. This supports the need for further studies to investigate the role of behavioural interventions for nonmotor symptoms.


Fine-Tuning the Cr3+ R1-Line by Controlling Pauli Antisymmetry Strength.
Fine-tuning of the Cr3+ zero-phonon R1-line fluorescence (2E-4A2) has recently been achieved by varying the composition of Cr-doped solid solution garnets. Chemical substitutions of Y3+ with Lu3+ and Tb3+ produce R1-line shifts and multiplets that cannot be associated with direct or indirect changes in the Cr-O covalency alone and raise important questions on the nature of the interactions between the CrO6 active center and its environment, hence on the impact of local disorder. In this Letter we show that Pauli antisymmetry interactions with next-nearest neighbor ions, which are commonly omitted from theoretical analyses, induce a nephelauxetic effect on the CrO6 active center that shifts the R1-line. The strength of these interactions increases with the ionic radius and number of codopant ions, all of it resulting in controlled shifts and multiplets of R1-lines. The Pauli antisymmetry induced nephelauxetic effect, combined with the R1-line shift with lattice constant, allows for a very fine-tuning of the Cr3+ R1-line.


TRAL: tandem repeat annotation library.
Currently, more than 40 sequence tandem repeat detectors are published, providing heterogeneous, partly complementary, partly conflicting results. We present TRAL, a tandem repeat annotation library that allows running and parsing of various detection outputs, clustering of redundant or overlapping annotations, several statistical frameworks for filtering false positive annotations, and importantly a tandem repeat annotation and refinement module based on circular profile hidden Markov models (cpHMMs). Using TRAL, we evaluated the performance of a multi-step tandem repeat annotation workflow on 547 085 sequences in UniProtKB/Swiss-Prot. The researcher can use these results to predict run-times for specific datasets, and to choose annotation complexity accordingly. TRAL is an open-source Python 3 library and is available, together with documentation and tutorials via http://www.vital-it.ch/software/tral. firstname.lastname@example.com.


A key role for similarity in vicarious reward.
Humans appear to have an inherent prosocial tendency toward one another in that we often take pleasure in seeing others succeed. This fact is almost certainly exploited by game shows, yet why watching others win elicits a pleasurable vicarious rewarding feeling in the absence of personal economic gain is unclear. One explanation is that game shows use contestants who have similarities to the viewing population, thereby kindling kin-motivated responses (for example, prosocial behavior). Using a game show-inspired paradigm, we show that the interactions between the ventral striatum and anterior cingulate cortex subserve the modulation of vicarious reward by similarity, respectively. Our results support studies showing that similarity acts as a proximate neurobiological mechanism where prosocial behavior extends to unrelated strangers.


Towards More Comprehensive Projections of Urban Heat-Related Mortality: Estimates for New York City under Multiple Population, Adaptation, and Climate Scenarios.
High temperatures have substantial impacts on mortality and, with growing concerns about climate change, numerous studies have developed projections of future heat-related deaths around the world. Projections of temperature-related mortality are often limited by insufficient information to formulate hypotheses about population sensitivity to high temperatures and future demographics. The present study derived projections of temperature-related mortality in New York City by taking into account future patterns of adaptation or demographic change, both of which can have profound influences on future health burdens. We adopted a novel approach to modeling heat adaptation by incorporating an analysis of the observed population response to heat in New York City over the course of eight decades. This approach projected heat-related mortality until the end of the 21st century based on observed trends in adaptation over a substantial portion of the 20th century. In addition, we incorporated a range of new scenarios for population change until the end of the 21st century. We then estimated future heat-related deaths in New York City by combining the changing temperature-mortality relationship and population scenarios with downscaled temperature projections from the 33 global climate models (GCMs) and two Representative Concentration Pathways (RCPs). The median number of projected annual heat-related deaths across the 33 GCMs varied greatly by RCP and adaptation and population change scenario, ranging from 167 to 3,331 in the 2080s compared with 638 heat-related deaths annually between 2000 and 2006. These findings provide a more complete picture of the range of potential future heat-related mortality risks across the 21st century in New York City, and they highlight the importance of both demographic change and adaptation responses in modifying future risks. Citation: Petkova EP, Vink JK, Horton RM, Gasparrini A, Bader DA, Francis JD, Kinney PL. 2017. Towards more comprehensive projections of urban heat-related mortality: estimates for New York City under multiple population, adaptation, and climate scenarios. Environ Health Perspect 125:47-55; http://dx.doi.org/10.1289/EHP166.


Evaluation of rumen fatty acid hydrogenation intermediates and differences in bacterial communities after feeding wheat- or corn-based dried distillers grains to feedlot cattle.
The effect of partially replacing rolled barley (86.6% of control diet) with 20% wheat dried distillers grains plus solubles (DDGS), 40% wheat DDGS, 20% corn DDGS, or 40% corn DDGS (dietary DM basis) on rumen fluid fatty acid (FA) composition and some rumen bacterial communities was evaluated using 100 steers (20 per treatment). Wheat DDGS increased the 11t- to 10t-18:1 ratio (P < 0.05) in rumen fluid and there was evidence that the conversion of trans-18:1 to 18:0 was reduced in the control and wheat DDGS diets but not in the corn DDGS diet. Bacterial community profiles obtained using denaturing gradient gel electrophoresis and evaluated by Pearson correlation similarity matrices were not consistent for diet and, therefore, these could not be linked to different specific rumen FA. This inconsistency may be related to the nature of diets fed (dominant effect of barley), limited change in dietary composition as the result of DDGS inclusion, large animal-to-animal variation, and possibly additional stress as a result of transport just before slaughter. Ruminal densities of a key fiber-digesting bacteria specie that produces 11t-18:1 from linoleic and linolenic acids (Butyrivibrio fibrisolvens), and a lactate producer originally thought responsible for production of 10t,12c-18:2 (Megasphaera elsdenii) were not influenced by diet (P > 0.05).


Interaction between loggerhead sea turtles (Caretta caretta) and marine litter in Sardinia (Western Mediterranean Sea).
Anthropogenic debris in the environment affects many species that accidentally ingest it. The aim of this study is to evaluate the quantity and composition of marine litter ingested by loggerheads in Sardinia, thus supplying for the lack of data in the existing literature for this area. Seventeen of the 121 (14.04%) monitored turtles presented debris in their digestive tracts. Litter in faecal pellet of alive individuals (n = 91) and in gastro-intestinal contents of dead ones (n = 30) was categorized, counted and weighed. User plastic was the main category of ingested debris with a frequency of occurrence of 13.22% of the total sample, while sheet (12.39%) and fragments (9.09%) were the most relevant sub-categories. This study highlights for the first time the incidence of litter in alive turtles in Sardinia. This contribution improves the knowledge about marine litter interaction on Caretta caretta as bio-indicator. Results will be useful for the Marine Strategy implementation.


Differential effects of formoterol on thrombin- and PDGF-induced proliferation of human pulmonary arterial vascular smooth muscle cells.
Increased pulmonary arterial vascular smooth muscle (PAVSM) cell proliferation is a key pathophysiological component of pulmonary vascular remodeling in pulmonary arterial hypertension (PH). The long-acting β2-adrenergic receptor (β2AR) agonist formoterol, a racemate comprised of (R,R)- and (S,S)-enantiomers, is commonly used as a vasodilator in chronic obstructive pulmonary disease (COPD). PH, a common complication of COPD, increases patients' morbidity and reduces survival. Recent studies demonstrate that formoterol has anti-proliferative effects on airway smooth muscle cells and bronchial fibroblasts. The effects of formoterol and its enantiomers on PAVSM cell proliferation are not determined. The goals of this study were to examine effects of racemic formoterol and its enantiomers on PAVSM cell proliferation as it relates to COPD-associated PH. Basal, thrombin-, PDGF- and chronic hypoxia-induced proliferation of primary human PAVSM cells was examined by DNA synthesis analysis using BrdU incorporation assay. ERK1/2, mTORC1 and mTORC2 activation were determined by phosphorylation levels of ERK1/2, ribosomal protein S6 and S473-Akt using immunoblot analysis. We found that (R,R) and racemic formoterol inhibited basal, thrombin- and chronic hypoxia-induced proliferation of human PAVSM cells while (S,S) formoterol had lesser inhibitory effect. The β2AR blocker propranolol abrogated the growth inhibitory effect of formoterol. (R,R), but not (S,S) formoterol attenuated basal, thrombin- and chronic hypoxia-induced ERK1/2 phosphorylation, but had little effect on Akt and S6 phosphorylation levels. Formoterol and its enantiomers did not significantly affect PDGF-induced DNA synthesis and PDGF-dependent ERK1/2, S473-Akt and S6 phosphorylation in human PAVSM cells. Formoterol inhibits basal, thrombin-, and chronic hypoxia-, but not PDGF-induced human PAVSM cell proliferation and ERK1/2, but has little effect on mTORC1 and mTORC2 signaling. Anti-proliferative effects of formoterol depend predominantly on its (R,R) enantiomer and require the binding with β2AR. These data suggest that (R,R) formoterol may be considered as potential adjuvant therapy to inhibit PAVSM cell proliferation in COPD-associated PH.


Perceiving and acting upon weight illusions in the absence of somatosensory information.
When lifting novel objects, individuals' fingertip forces are influenced by a variety of cues such as volume and apparent material. This means that heavy-looking objects tend to be lifted with more force than lighter-looking objects, even when they weigh the same amount as one another. Expectations about object weight based on visual appearance also influence how heavy an object feels when it is lifted. For instance, in the "size-weight illusion," small objects feel heavier than equally weighted large objects. Similarly, in the "material-weight illusion," objects that seem to be made from light-looking materials feel heavier than objects of the same weight that appear to be made from heavy-looking materials. In this study, we investigated these perceptual and sensorimotor effects in IW, an individual with peripheral deafferentation (i.e., a loss of tactile and proprioception feedback). We examined his perceptions of heaviness and fingertip force application over repeated lifts of objects that varied in size or material properties. Despite being able to report real weight differences, IW did not appear to experience the size- or material-weight illusions. Furthermore, he showed no evidence of sensorimotor prediction based on size and material cues. The results are discussed in the context of forward models and their possible influence on weight perception and fingertip force control.


Effect of dietary supplementation of different oils during the first or second half of pregnancy on the glucose tolerance of the sow.
Poor glucose tolerance may be an under-researched contributory factor in the high (10% to 20%) pre-weaning mortality rate observed in pigs. Insulin resistance commences at around week 12 of gestation in the sow, although there are conflicting reports in the literature about the extent to which insulin resistance is modulated by maternal diet. The aim of the study was to determine the effects of supplementing the maternal diet with different dietary oils during either the first half or the second half of gestation on the glucose tolerance of the sow. Sows were offered the control (C: n = 5) diet as pellets or the C diet plus 10% extra energy (n = 16 per group) derived from either: (i) extra pellets; (ii) palm oil; (iii) olive oil; (iv) sunflower oil; or (v) fish oil. Experimental diets were fed during either the first (G1) or second (G2) half of gestation. A glucose tolerance test (GTT) was conducted on day 108 of gestation by administering 0.5 g/kg glucose i.v. Blood samples were taken every 5 to 10 min for 90 min post administration. The change in body weight and backfat thickness during gestation was similar but both type and timing of dietary supplementation influenced litter size and weight. With the exception of the sunflower oil group, supplementing the maternal diet in G1 resulted in larger and heavier litters, particularly in mothers offered palm oil. Basal blood glucose concentrations tended to be more elevated in G1 than G2 groups, whilst plasma insulin concentrations were similar. Following a GTT, the adjusted area under the curve was greater in G1 compared to G2 sows, despite no differences in glucose clearance. Maternal diet appeared to influence the relationship between glucose curve characteristics following a GTT and litter outcome. In conclusion, the degree of insulin sensitivity can be altered by both the period during which maternal nutritional supplementation is offered and the fatty acid profile of the diet.


An HLA-D region restriction fragment length polymorphism associated with celiac disease.
This study is the first to describe a molecular marker that distinguishes the celiac disease HLA-D region haplotype from a serologically identical haplotype in unaffected controls. Using a DQ beta chain cDNA probe and the restriction endonuclease Rsa I, we have detected a polymorphic 4.0 kb fragment which, in DQw2 individuals, is associated with a 40-fold increased relative risk of developing celiac disease. This finding should permit the identification of the celiac disease susceptibility gene(s) in the HLA-D region and facilitate a more precise dissection of the molecular and immunogenetic mechanisms involved in the pathogenesis of that disease.


Strike-Slip Displacement on Faults in Triassic Rocks in New Jersey.
The Hopewell and Flemington faults in New Jersey are inferred to extend 10 to 15 miles or more farther north than their previously mapped northward limits. The Hopewell fault, previously known to show dip-slip displacement of 10,000 feet or more, is inferred to include as well a right-lateral strike-slip component of 12 miles on the basis of apparent displacement along its northern extension of the crestal traces of two partial anticlines which are held to be displaced segments of the same transverse structure, here called the Somerville anticline. An unknown amount of strike-slip displacement may have occurred also on the Flemington fault, if the apparent offset of the Ramapo fault at the northwestern border of the Triassic outcrop belt is explained as the result of displacement of a formerly continuous northeast-trending, southeast-dipping fault by a north-trending vertical extension of the Flemington fault.