The effect of a natural molecule in ovary ischemia reperfusion damage: does lycopene protect ovary?
Ovarian ischemia is a gynecological emergency case that occurs as a result of ovarian torsion. Oxidative stress plays a central role in the development of ischemia/reperfusion (IR) injuries. Lycopene (LYC) is a lipophilic, natural carotenoid well known for its antioxidant properties. This study provides information on the potential applications of lycopene. The Wistar Albino rats were distributed into six groups: Sham group (only a laparotomy was performed), Control group [laparotomy and intraperitoneal dissolvent (olive oil)], IR group, IR+olive oil group, IR+LYC 2.5 mg/kg/dose, intraperitoneal group, IR+LYC 5 mg/kg/dose intraperitoneal group. Evaluated in terms of histopathological changes, tissue malondialdehyde levels (MDA), ovarian expressions of phosphorylated nuclear factor-kappa B (p-NF-κB) and the TUNEL method was utilized to show apoptosis of ovarian tissue. There was a significant decrease in MDA, p-NF-κB values and the proportion of apoptotic cells assessed by TUNEL compared to the group that did not receive intraperitoneal LYC in rat injury with IR damage (P<0.05). In histopathological damage scoring, it was observed that the cell damage was significantly reduced in LYC-administered groups. LYC showed significant ameliorative effects on ovary injury caused by IR through acting as an antioxidant, antiinflammatory, and antiapoptotic agent.


Wavefront-guided LASIK for the correction of primary myopia and astigmatism a report by the American Academy of Ophthalmology.
To describe wavefront-guided (WFG) LASIK for the primary treatment of low to moderate levels of myopia and astigmatism and to examine the evidence on the safety and effectiveness of the procedure in comparison with conventional LASIK. Literature searches conducted in 2004, 2005, 2006, and 2007 retrieved 209 unique references from the PubMed and Cochrane Library databases. The panel selected 65 articles to review, and of these, chose 45 articles that they considered to be of sufficient clinical relevance to submit to the panel methodologist for review. During the review and preparation of this assessment, an additional 2 articles were included. A level I rating was assigned to properly conducted, well-designed, randomized clinical trials; a level II rating was assigned to well-designed cohort and case-controlled studies; and a level III rating was assigned to case series, case reports, and poorly designed prospective and retrospective studies. In addition, studies that were conducted by laser manufacturers before device approval (premarket approval) were reviewed as a separate category of evidence. The assessment describes studies reporting results of WFG LASIK clinical trials, comparative trials, or both of WFG and conventional LASIK that were rated level II and level III. There were no studies rated as level I evidence. Four premarket approval studies conducted by 4 laser manufacturers were included in the assessment. The assessment did not compare study results or laser platforms because there were many variables, including the amount of follow-up, the use of different microkeratomes, and the level of preoperative myopia and astigmatism. There is substantial level II and level III evidence that WFG LASIK is safe and effective for the correction of primary myopia or primary myopia and astigmatism and that there is a high level of patient satisfaction. Microkeratome and flap-related complications are not common but can occur with WFG LASIK, just as with conventional LASIK. The WFG procedure seems to have similar or better refractive accuracy and uncorrected visual acuity outcomes compared with conventional LASIK. Likewise, there is evidence of improved contrast sensitivity and fewer visual symptoms, such as glare and halos at night, compared with conventional LASIK. Even though the procedure is designed to measure and treat both lower- and higher-order aberrations (HOAs), the latter are generally increased after WFG LASIK. The reasons for the increase in HOA are likely multifactorial, but the increase typically is less than that induced by conventional LASIK. No long-term assessment of WFG LASIK was possible because of the relatively short follow-up (12 months or fewer) of most of the studies reviewed.


Genetic Test Reporting and Counseling for Melanoma Risk in Minors May Improve Sun Protection Without Inducing Distress.
Genetic testing of minors is advised only for conditions in which benefits of early intervention outweigh potential psychological harms. This study investigated whether genetic counseling and test reporting for the CDKN2A/p16 mutation, which confers highly elevated melanoma risk, improved sun protection without inducing distress. Eighteen minors (Mage = 12.4, SD = 1.9) from melanoma-prone families completed measures of protective behavior and distress at baseline, 1 week (distress only), 1 month, and 1 year following test disclosure. Participants and their mothers were individually interviewed on the psychological and behavioral impact of genetic testing 1 month and 1 year post-disclosure. Carriers (n = 9) and noncarriers (n = 9) reported significantly fewer sunburns and a greater proportion reported sun protection adherence between baseline and 1 year post-disclosure; results did not vary by mutation status. Anxiety symptoms remained low post-disclosure, while depressive symptoms and cancer worry decreased. Child and parent interviews corroborated these findings. Mothers indicated that genetic testing was beneficial (100%) because it promoted risk awareness (90.9%) and sun protection (81.8%) without making their children scared (89.9%); several noted their child's greater independent practice of sun protection (45.4%). In this small initial study, minors undergoing CDKN2A/p16 genetic testing reported behavioral improvements and consistently low distress, suggesting such testing may be safely implemented early in life, allowing greater opportunity for risk-reducing lifestyle changes.


Ultrastructural and Cytological Studies on Mycosphaerella pinodes Infection of the Model Legume Medicago truncatula.
Ascochyta (Mycosphaerella) blight on cultivated peas is primarily caused by infection through asexual spores (pycnospores) of Mycosphaerella pinodes (Berk. et Blox.) Vestergren [recently renamed Peyronellaea pinodes (Berk. & A. Bloxam) Aveskamp, Gruyter & Verkley]. Using a model pathosystem involving Medicago truncatula and Mycosphaerella pinodes strain OMP-1, we examined the histology and ultrastructure of early infection events and fungal development including penetration by appressoria, vegetative growth of infection hyphae, and host responses. On the susceptible ecotype R108-1, pycnospores germinated and grew over the surface of the epidermis, then formed an appressoria and penetrated the cuticle. Beneath the cuticle, the infection peg expanded into a hyphae that grew within the outer wall of the epidermis. Subsequently, the hyphae penetrated down within mesophyll cells and proliferated vigorously, eventually, forming asexual fruiting bodies (pycnidia). In contrast, successful penetration and subsequent growth of infection hyphae were considerably restricted in the ecotype Caliph. Detected by its reaction with cerium chloride (CeCl3) to generate electron-dense cerium perhydroxides in transmission electron micrographs, hydrogen peroxide (H2O2) accumulated in epidermal and mesophyll cells of Caliph challenged with pycnospores of M. pinodes. This intracellular localization was confirmed by energy-dispersive X-ray spectroscopy. Our observations thus indicate that the oxidative burst reaction leading to the generation of reactive oxygen species is associated with a local host defense response in Caliph, since no clear H2O2 accumulation was detectable in susceptible R108-1. Indeed, aberrant hyphae such as intrahyphal hyphae and dead hyphae, probably due to a local defense elicited by the fungus, were abundant in Caliph but not in R108-1. Our results on the cellular interactions between the fungus and host cells provide additional insights to understand foliar infection by M. pinodes on cultivated peas.


Abide with me: religious group identification among older adults promotes health and well-being by maintaining multiple group memberships.
Aging is associated with deterioration in health and well-being, but previous research suggests that this can be attenuated by maintaining group memberships and the valued social identities associated with them. In this regard, religious identification may be especially beneficial in helping individuals withstand the challenges of aging, partly because religious identity serves as a basis for a wider social network of other group memberships. This paper aims to examine relationships between religion (identification and group membership) and well-being among older adults. The contribution of having and maintaining multiple group memberships in mediating these relationships is assessed, and also compared to patterns associated with other group memberships (social and exercise). Study 1 (N = 42) surveyed older adults living in residential care homes in Canada, who completed measures of religious identity, other group memberships, and depression. Study 2 (N = 7021) longitudinally assessed older adults in the UK on similar measures, but with the addition of perceived physical health. In Study 1, religious identification was associated with fewer depressive symptoms, and membership in multiple groups mediated that relationship. However, no relationships between social or exercise groups and mental health were evident. Study 2 replicated these patterns, but additionally, maintaining multiple group memberships over time partially mediated the relationship between religious group membership and physical health. Together these findings suggest that religious social networks are an especially valuable source of social capital among older adults, supporting well-being directly and by promoting additional group memberships (including those that are non-religious).


Circadian affective, cardiopulmonary, and cortisol variability in depressed and nondepressed individuals at risk for cardiovascular disease.
Depression is a risk factor for cardiovascular disease (CVD) perhaps mediated by hypothalamic-pituitary-adrenal (HPA) axis or vagal dysregulation. We investigated circadian mood variation and HPA-axis and autonomic function in older (55 years) depressed and nondepressed volunteers at risk for CVD by assessing diurnal positive and negative affect (PA, NA), cortisol, and cardiopulmonary variables in 46 moderately depressed and 19 nondepressed volunteers with elevated CVD risk. Participants sat quietly for 5-min periods (10:00, 12:00, 14:00, 17:00, 19:00, and 21:00), and then completed an electronic diary assessing PA and NA. Traditional and respiration-controlled heart rate variability (HRV) variables were computed for these periods as an index of vagal activity. Salivary cortisols were collected at waking, waking+30min, 12:00, 17:00, and 21:00h. Cortisol peaked in the early morning after waking, and gradually declined over the day, but did not differ between groups. PA was lower and NA was higher in the depressed group throughout the day. HRV did not differ between groups. Negative emotions were inversely related to respiratory sinus arrhythmia in nondepressed participants. We conclude that moderately depressed patients do not show abnormal HPA-axis function. Diurnal PA and NA distinguish depressed from nondepressed individuals at risk for CVD, while measures of vagal regulation, even when controlled for physical activity and respiratory confounds, do not. Diurnal mood variations of older individuals at risk for CVD differ from those reported for other groups and daily fluctuations in NA are not related to cardiac autonomic control in depressed individuals.


Applications and biomonitoring issues of recombinant erythropoietins for doping control.
The biochemical actions and side effects of recombinant erythropoietins (rhEPOs), their analogs and mimetics, their misuse as doping agents, and the principal analytical strategies developed to identify them in athletes' biologic fluids are reviewed. Patients who experience a range of pathologies have benefited from the administration of rhEPOs to correct severe anemia. Currently, monitoring the biologic effect of rhEPO in patients under treatment is by measuring the hemoglobin concentration. However, it may be valuable to directly monitor the actual levels of the administered drug and determine a dose-dependent correlation with any clinical adverse effect observed. This may permit the adoption of a patient-specific administration regime. Currently, the method of detecting EPO approved for doping control is an isoelectric-focusing, double-blotting, chemiluminescence assay based on charge differences between isoforms of rhEPOs and endogenous EPO in urine. The advantages and limitations of this method are presented. A new approach using sodium dodecyl sulfate-polyacrylamide gel electrophoresis as a complementary tool to the established method is discussed. The application of matrix-assisted laser desorption/ionization mass spectrometry and liquid chromatography combined with tandem mass spectrometry for the direct detection of the rhEPO molecules may prove to be promising. Indirect evidence of rhEPO abuse by athletes is based on the analysis of blood parameters (hemoglobin hematocrit, reticulocytes, macrocytes, etc) and serum markers (concentration of EPO and serum transferrin receptors, etc). Enrichment of the screened parameters with gene or biochemical markers revealing altered erythropoiesis and adoption of longitudinal monitoring of athletes' hematologic and biochemical parameters could also be a complementary approach in the fight against doping.


Promoting family-centered visitation makes a difference.
Promoting parental and sibling visitation of the critically ill child can positively influence the resolution of a crisis when a child is admitted to the pediatric intensive care unit. There are many benefits as well as barriers to incorporating family-centered visitation into the plan of care. Understanding the needs, stressors, and coping styles of the entire family will help the nurse provide a positive experience when parents or siblings visit the critically ill child.


Assessing volume of accelerometry data for reliability in preschool children.
This study examines what volume of accelerometry data (h·d) is required to reliably estimate preschool children's physical activity and whether it is necessary to include weekday and weekend data. Accelerometry data from 493 to 799 (depending on wear time) preschool children from the Melbourne-based Healthy Active Preschool Years study were used. The percentage of wear time each child spent in total (light-vigorous) physical activity was the main outcome. Hourly increments of daily data were analyzed. t-tests, controlling for age and clustering by center of recruitment, assessed the differences between weekday and weekend physical activity. Intraclass correlation coefficients estimated reliability for an individual day. Spearman-Brown prophecy formula estimated the number of days required to reach reliability estimates of 0.7, 0.8, and 0.9. The children spent a significantly greater percentage of time being physically active on weekend compared with weekdays regardless of the minimum number of hours included (t = 12.49-16.76, P < 0.001 for all). The number of days required to reach each of the predetermined reliability estimates increased as the number of hours of data per day decreased. For instance, 2.7-2.8 d of data were required to reach a reliability estimate of 0.7 with 10 or more hours of data per day; 3.3-3.4 d were required to meet the same reliability estimate for days with 7 h of data. Future studies should ensure they include the minimum amount of data (hours per day and number of days) as identified in this study to meet at least a 0.7 reliability level and should report the level of reliability for their study. In addition to weekdays, at least one weekend day should be included in analyses to reliably estimate physical activity levels for preschool children.


The fast polarization modulation based dual-focus fluorescence correlation spectroscopy.
We introduce two new alternative experimental realizations of dual focus fluorescence correlation spectroscopy (2fFCS), a method which allows for obtaining absolute diffusion coefficient of fast moving fluorescing molecules at nanomolar concentrations, based on fast polarization modulation of the excitation beam by a resonant electro-optical modulator. The first approach rotates every second linearly polarized laser pulse by 90 degrees to obtain independent intensity readout for both foci, similar to original design. The second approach combines polarization modulation of cw laser and fluorescence lifetime correlation spectroscopy (FLCS) like analysis to obtain clean correlation curves for both overlapping foci. We tested our new approaches with different lasers and samples, revealed a need for intensity cross-talk corrections by comparing the methods with each other and discussed experimental artifacts stemming from improper polarization alignment and detector afterpulsing. The advantages of our solutions are that the polarization rotation approach requires just one pulsed laser for each wavelength, that the polarization modulation approach even mitigates the need of pulsed lasers by using standard cw lasers and that it allows the DIC prism to be placed at an arbitrary angle. As a consequence the presented experimental solutions for 2fFCS can be more easily implemented into commercial laser scanning microscopes.


FK506 binding protein 12 is expressed in rat penile innervation and upregulated after cavernous nerve injury.
To evaluate whether FK506 and other immunophilin ligands may have potential therapeutic efficacy for erectile function preservation after penile nerve injury, we demonstrated localizations of the immunophilin FK506 binding protein 12 (FKBP 12) in intact and injured rat penile nerves and correlated these findings with localizations of neuronal nitric oxide synthase (nNOS), which neuronally forms nitric oxide for mediation of penile erection, in response to systemically administered FK506. Adult male Sprague-Dawley rats were subjected to unilateral right cavernous nerve forceps crush injury and administered FK506 (1 mg/kg i.p.) or saline at the same time and daily up to 7 days. At 1, 3 and 7 days after injury, bilateral cavernous nerves and major pelvic ganglia were collected for nNOS immunohistochemistry, FKBP 12 immunohistochemistry, and FKBP 12 in situ hybridisation. Protein expressions of nNOS and FKBP 12 were observed in major pelvic ganglion, cavernous nerve and nerve terminals within the rat penis as well as mRNA expression of FKBP 12 observed in the rat major pelvic ganglion neuronal cell bodies to a minimal extent at baseline conditions. After cavernous nerve injury, nNOS immunoreactivity was observed to be slightly diminished in ipsilateral penile nerve structures at only one day following injury while both FKBP 12 protein and mRNA expressions were observed to be increased at each interval of study. FK506 treatment did not affect staining of intact or injured nerves. Our demonstration that FKBP 12 is localized to penile innervation in the rat and becomes upregulated following cavernous nerve crush injury, independent of FK506 treatment, suggests that this immunophilin mediates a neurotrophic mechanism. Whether FK506 affords neuroprotection that preserves penile erection through FKBP 12 upregulation is unclear.


Factors affecting farmers' use of organic and inorganic fertilizers in South Asia.
Fertilizer, though one of the most essential inputs for increasing agricultural production, is a leading cause of nitrous oxide emissions from agriculture, contributing significantly to global warming. Therefore, understanding factors affecting farmers' use of fertilizers is crucial to develop strategies to improve its efficient use and to minimize its negative impacts. Using data from 2528 households across the Indo-Gangetic Plains in India, Nepal, and Bangladesh, this study examines the factors affecting farmers' use of organic and inorganic fertilizers for the two most important cereal crops - rice and wheat. Together, these crops provide the bulk of calories consumed in the region. As nitrogen (N) fertilizer is the major source of global warming and other environmental effects, we also examine the factors contributing to its overuse. We applied multiple regression models to understand the factors influencing the use of inorganic fertilizer, Heckman models to understand the likelihood and intensity of organic fertilizer (manure) use, and a probit model to examine the over-use of N fertilizer. Our results indicate that various socio-economic and geographical factors influence the use of organic and inorganic fertilizers in rice and wheat. Across the study sites, N fertilizer over-use is the highest in Haryana (India) and the lowest in Nepal. Across all locations, farmers reported a decline in manure application, concomitant with a lack of awareness of the principles of appropriate fertilizer management that can limit environmental externalities. Educational programs highlighting measures to improving nutrient-use-efficiency and reducing the negative externalities of N fertilizer over-use are proposed to address these problems.


Early Antibiotics and Childhood Obesity: Do Future Risks Matter to Parents and Physicians?
To understand how parents and physicians make decisions regarding antibiotics and whether a potential associated risk of obesity would alter decisions, we conducted a qualitative study of parents and physicians who care for children. Parent focus groups and physician interviews used a guide focused on experience with antibiotics and perceptions of risks and benefits, including obesity. Content analysis was used to understand how a risk of obesity would influence antibiotic decisions. Most parents (n = 59) and physicians (n = 22) reported limited discussion about any risks at the time of antibiotic prescriptions. With an acute illness, most parents prioritized symptomatic improvement and chose to start antibiotics. Physicians' treatment preferences were varied. An obesity risk did not change most parents' or physicians' preferences. Given that parent-physician discussion at the time of acute illness is unlikely to change preferences, public health messaging may be a more successful approach to counter obesity and antibiotics overuse.


Hepatitis C virus infection promotes hepatic gluconeogenesis through an NS5A-mediated, FoxO1-dependent pathway.
Chronic hepatitis C virus (HCV) infection is often associated with type 2 diabetes. However, the precise mechanism underlying this association is still unclear. Here, using Huh-7.5 cells either harboring HCV-1b RNA replicons or infected with HCV-2a, we showed that HCV transcriptionally upregulated the genes for phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase), the rate-limiting enzymes for hepatic gluconeogenesis. In this way, HCV enhanced the cellular production of glucose 6-phosphate (G6P) and glucose. PEPCK and G6Pase gene expressions are controlled by the transcription factor forkhead box O1 (FoxO1). We observed that although neither the mRNA levels nor the protein levels of FoxO1 expression were affected by HCV, the level of phosphorylation of FoxO1 at Ser319 was markedly diminished in HCV-infected cells compared to the control cells, resulting in an increased nuclear accumulation of FoxO1, which is essential for sustaining its transcriptional activity. It was unlikely that the decreased level of FoxO1 phosphorylation was mediated through Akt inactivation, as we observed an increased phosphorylation of Akt at Ser473 in HCV-infected cells compared to control cells. By using specific inhibitors of c-Jun N-terminal kinase (JNK) and reactive oxygen species (ROS), we demonstrated that HCV infection induced JNK activation via increased mitochondrial ROS production, resulting in decreased FoxO1 phosphorylation, FoxO1 nuclear accumulation, and, eventually, increased glucose production. We also found that HCV NS5A mediated increased ROS production and JNK activation, which is directly linked with the FoxO1-dependent increased gluconeogenesis. Taken together, these observations suggest that HCV promotes hepatic gluconeogenesis through an NS5A-mediated, FoxO1-dependent pathway.


[The effects of smokeless tobacco "Maras powder" and smoking on aortic elasticity in young adults].
Stiffness index beta (SIB), aortic strain (AS) and distensibility (AD) are the parameters used to assess elasticity of the aorta, and can be measured by non-invasive method such as echocardiography. In this study, we aimed to analyse the effects of Maraş powder and smoking on aortic stiffness by comparing young individuals. The study included 90 male subjects aged 18-40 years. 30 subjects were Maras powder users (mean age; 32±2), 30 were smokers (mean age: 28±2) and 30 were healthy volunteers (mean age: 29±2). After detailed physical examination, all subjects underwent transthoracic echocardiography. Systolic and diastolic diameters of the aorta were measured from the ascending aorta at modified parasternal long axis views by M-mode echocardiography. AS, AD, and SIB were calculated using standard formulae. Group parameters were then compared to each other. There was no significant difference between the groups in terms of demographic and clinical features, including blood pressures, lipid profile and serum creatinine (p>0.05). Although AS and AD were lower, and SIB was higher in the Maraş powder and smoking groups compared to the control group, the difference between groups was not statistically significant (for AS: 17.61±2.22, 17.75±1.93, 18.48±2.02 respectively, for AD: 9.03±1.12, 9.14±0.96, 9.9±1.12, respectively, for SIB: 2.72±1.07, 2.59±0.88, 2.37±0.71 respectively, for all p>0.05). Our study revealed that smoking and Maraş powder did not lead to a significant change in elasticity of the aorta in individuals under the age of 40.


Impact of (chemo)radiotherapy on immune cell composition and function in cervical cancer patients.
New treatments based on combinations of standard therapeutic modalities and immunotherapy are of potential use, but require a profound understanding of immune modulatory properties of standard therapies. Here, the impact of standard (chemo)radiotherapy on the immune system of cervical cancer patients was evaluated. Thirty patients with cervical cancer were treated with external beam radiation therapy (EBRT), using conventional three-dimensional or intensity modulated radiation therapy without constraints for bone marrow sparing. Serial blood sampling for immunomonitoring was performed before, midway and at 3, 6 and 9 weeks after EBRT to analyze the composition of lymphocyte and myeloid-cell populations, the expression of co-stimulatory molecules, T-cell reactivity and antigen presenting cell (APC) function. Therapy significantly decreased the absolute numbers of circulating leukocytes and lymphocytes. Furthermore, the capacity of the remaining T cells to respond to antigenic or mitogenic stimulation was impaired. During treatment the frequency of both CD4+ and CD8+ T cells dropped and CD4+ T cells displayed an increased expression of programmed cell death-1 (PD-1). In vitro blocking of PD-1 successfully increased T-cell reactivity in all five samples isolated before radiotherapy but was less successful in restoring reactivity in samples isolated at later time points. Moreover, (chemo)radiotherapy was associated with an increase in both circulating monocytes and myeloid-derived suppressor cells (MDSCs) and an impaired capacity of APCs to stimulate allogeneic T cells. T-cell reactivity was slowly restored at 6-9 weeks after cessation of therapy. We conclude that conventional (chemo)radiotherapy profoundly suppresses the immune system in cervical cancer patients, and may restrict its combination with immunotherapy.


STAT1 is required for redifferentiation during Madin-Darby canine kidney tubulogenesis.
Tubule formation in vitro using Madin-Darby canine kidney (MDCK) epithelial cells consists mainly of two processes. First, the cells undergo a partial epithelial-mesenchymal transition (pEMT), losing polarity and migrating. Second, the cells redifferentiate, forming cords and then tubules with continuous lumens. We have shown previously that extracellular signal-regulated kinase activation is required for pEMT. However, the mechanism of how the pEMT phase is turned off and the redifferentiation phase is initiated is largely unknown. To address the central question of the sequential control of these two phases, we used MDCK cells grown as cysts and treated with hepatocyte growth factor to model tubulogenesis. We show that signal transducer and activator of transcription (STAT)1 controls the sequential progression from the pEMT phase to the redifferentiation phase. Loss of STAT1 prevents redifferentiation. Constitutively active STAT1 allows redifferentiation to occur even when cells are otherwise prevented from progressing beyond the pEMT phase by exogenous activation of Raf. Moreover, tyrosine phosphorylation defective STAT1 partially restored cord formation in such cells, suggesting that STAT1 functions in part as nonnuclear protein mediating signal transduction in this process. Constitutively active or inactive forms of STAT1 did not promote lumen maturation, suggesting this requires a distinct signal.


Solution structure by NMR of circulin A: a macrocyclic knotted peptide having anti-HIV activity.
The three-dimensional solution structure of circulin A, a 30 residue polypeptide from the African plant Chassalia parvifolia, has been determined using two-dimensional 1H-NMR spectroscopy. Circulin A was originally identified based upon its inhibition of the cytopathic effects and replication of the human immunodeficiency virus. Structural restraints consisting of 369 interproton distances inferred from nuclear Overhauser effects, and 21 backbone dihedral and nine chi1 angle restraints from spin-spin coupling constants were used as input for simulated annealing calculations and energy minimisation in the program X-PLOR. The final set of 12 structures had mean pairwise rms differences over the whole molecule of 0.91 A for the backbone atom, and 1.68 A for all heavy atoms. For the well-defined region encompassing residues 2-12 and 18-27, the corresponding values were 0.71 and 1.66 A, respectively. Circulin A adopts a compact structure consisting of beta-turns and a distorted segment of triple-stranded beta-sheet. Fluorescence spectroscopy provided additional evidence for a solvent-exposed Trp residue. The molecule is stabilised by three disulfide bonds, two of which form an embedded loop completed by the backbone fragments connecting the cysteine residues. A third disulfide bond threads through the centre of this loop to form a "cystine-knot" motif. This motif is present in a range of other biologically active proteins, including omega-contoxin GVIA and Cucurbita maxima trypsin inhibitor. Circulin A belongs to a novel class of macrocyclic peptides which have been isolated from plants in the Rubiaceae family. The global fold of circulin A is similar to kalata B1, the only member of this class for which a structure has previously been determined.


A lentiviral RNAi library for human and mouse genes applied to an arrayed viral high-content screen.
To enable arrayed or pooled loss-of-function screens in a wide range of mammalian cell types, including primary and nondividing cells, we are developing lentiviral short hairpin RNA (shRNA) libraries targeting the human and murine genomes. The libraries currently contain 104,000 vectors, targeting each of 22,000 human and mouse genes with multiple sequence-verified constructs. To test the utility of the library for arrayed screens, we developed a screen based on high-content imaging to identify genes required for mitotic progression in human cancer cells and applied it to an arrayed set of 5,000 unique shRNA-expressing lentiviruses that target 1,028 human genes. The screen identified several known and approximately 100 candidate regulators of mitotic progression and proliferation; the availability of multiple shRNAs targeting the same gene facilitated functional validation of putative hits. This work provides a widely applicable resource for loss-of-function screens, as well as a roadmap for its application to biological discovery.


Modeling the distinct pathways of influence of coping strategies on youth suicidal ideation: a national longitudinal study.
National surveys indicate high rates of suicidal ideation in youth, especially among females. Coping skill training programs hold promise as a potential intervention that can help young people better manage stress and not consider suicide as a solution to life's problems. To assess the promise of this strategy, the present research examined which coping strategies (if any) predicted reduction in youth suicidal ideation over a 1-year follow-up, and explored the potential pathways through which their influence was channeled. Two waves of panel data from a nationally representative sample of youth, assessed 1 year apart (N = 710; Mean age = 18 years) were analyzed separately by gender using multiple group path analytic procedures. Four coping strategies, namely problem solving, emotional regulation, support seeking and acceptance were found to predict reduction in suicidal ideation among both males and females. However, the influence of these strategies (at baseline) was channeled through distinct pathways. The effect of emotional regulation (and acceptance) was channeled through its use at follow-up and was mediated by reductions in perceived stress and depressive symptoms, leading to reduction in suicidal ideation. The influence of support seeking was also channeled through its more recent use at follow-up, but directly predicted reduction in suicidal ideation, with no effect on perceived stress or depressive symptoms. The effect of problem solving on suicidal ideation was mediated by reduction in depressive symptoms, but was not channeled through its use at follow-up, suggesting a longer time course for the protective influence of this strategy. Finally, acceptance had a direct risk-enhancing effect on suicidal ideation. Coping strategies commonly used by youth can be effective in reducing suicidal ideation and therefore universal training in the effective use of these strategies should be considered. An understanding of the distinct pathways through which their effect on suicidal ideation is transmitted can better inform the design of youth suicide prevention interventions.


Cross-talk between G protein-coupled receptor and epidermal growth factor receptor signaling pathways contributes to growth and invasion of head and neck squamous cell carcinoma.
G protein-coupled receptors (GPCR) and the epidermal growth factor receptor (EGFR) are often both overexpressed and contribute to the growth of cancers by activating autocrine pathways. GPCR ligands have been reported to trigger EGFR signaling via receptor cross-talk in cancer cells. Here, we show that GPCR ligands prostaglandin E2 (PGE2) and bradykinin (BK) activate EGFR signaling. Inhibition of EGFR using several strategies, including small-molecule inhibitors and an EGFR-specific antibody, resulted in partial attenuation of signaling downstream of EGFR. PGE2 and BK triggered EGFR signaling by increasing selective autocrine release of transforming growth factor-alpha (TGF-alpha). Inhibition of tumor necrosis factor-alpha-converting enzyme abrogated BK- or PGE2-mediated activation of EGFR signaling. Both PGE2 and BK stimulated head and neck squamous cell carcinoma (HNSCC) invasion via EGFR. Treatment of HNSCC cells with the BK antagonist CU201 resulted in growth inhibition. The combination of CU201 with the EGFR small-molecule inhibitor erlotinib resulted in additive inhibitory effects on HNSCC cell growth in vitro. Inhibition of the PGE2 synthesis pathway with sulindac induced HNSCC cytotoxicity at high doses (EC(50), 620 micromol/L). However, combined inhibition of both EGFR with the tyrosine kinase inhibitor erlotinib and GPCR with sulindac at low doses of 6 and 310 micromol/L, respectively, resulted in synergistic killing of HNSCC tumor cells. Combined blockade of both EGFR and GPCRs may be a rational strategy to treat cancers, including HNSCC that shows cross-talk between GPCR and EGFR signaling pathways.


Do medical student attitudes towards patients with chronic low back pain improve during training? a cross-sectional study.
Health care professionals with positive attitudes towards the functional abilities of patients with low back pain are more likely to encourage activity and avoidance of rest as per recommended guidelines. This study investigated whether medical student training fosters positive attitudes towards patients with back pain and their ability to function. First (n = 202) and final (n = 146) year medical students at the University of Glasgow completed the Health Care Professionals' Pain and Impairment Relationship Scale (HC-PAIRS) questionnaire. This measures attitudes of clinicians towards the functional ability of patients with back pain. A group of first (n = 62) and final year (n = 61) business students acted as non-health care controls. Attitudes were compared using two-way ANOVA with year of study and discipline of degree as independent variables. Both year of study [F(1,465) = 39.5, p < 0.01] and discipline of degree [F(1,465) = 43.6, p < 0.01] had significant effects on total HC-PAIRS scores and there was a significant interaction effect [F(1,465) = 9.5, p < 0.01]. Medical students commenced their course with more positive attitudes than non-health care students (65.7 vs. 69.2 respectively; p < 0.01)--lower scores translating into more positive attitudes. In their final year, the difference between the two student groups had widened (56.4 vs. 65.3; p < 0.01). Undergraduate medical training promotes positive attitudes towards the functional ability of patients with back pain, suggesting that students may be more likely to develop an evidence-based approach to this patient group after qualification. Some adjustments to training may be warranted to encourage a more positive shift in attitudes.


The impact of the Maillard reaction on the in vitro proteolytic breakdown of bovine lactoferrin in adults and infants.
The Maillard reaction has been proposed as a natural pathway to functionalize proteins and modulate their proteolysis. Nevertheless, gaps in understanding the digestive fate of Maillard reaction products (MRPs) still exist, especially regarding bioactive proteins such as lactoferrin (LF). UV absorbance and SDS-PAGE were used to monitor reaction progression under mild thermal processing (60 °C, 79% RH). Dynamic light scattering showed that MRPs had increased colloidal size and turbidity at 3 < pH < 10. FRAP analysis and in vitro digestion experiments demonstrated that MRPs possessed improved antioxidant capacity and higher susceptibility to proteolysis to varying extents under adult conditions compared to infant conditions. Proteomic analyses of MRP digesta revealed altered enzymatic cleavage patterns with no pronounced changes in the formation of known bioactive peptides. These also indicated that MRPs may breakdown in the gastro-intestinal tract to potentially form novel bioactive peptides. Overall, this work highlights that the Maillard reaction could be harnessed to modify the extent of proteolysis and bioactivity of proteins.


Preservation of the greater occipital nerve during suboccipital craniectomy results in a paradoxical increase in postoperative headaches.
Injury to the greater occipital nerve (GON) during suboccipital/retrosigmoid craniectomy (SOC) has been postulated as an etiology of postoperative headaches (HAs). We hypothesized that severe postoperative HAs may be due to the division of the GON during dissection. To determine whether the GON plays an important role in the development of postoperative HAs. A retrospective review of prospectively accrued patients undergoing SOC by 1 neurosurgeon at Johns Hopkins from 1995 to 2009 was performed. A total of 280 patients were included in the study. HA was categorized into 3 groups according to the severity and impact on daily activities. Data were analyzed using a stepwise multivariate logistic regression analysis to identify independent factors associated with HA development. Patients with a history of preoperative HAs and migraine were excluded from the analysis. In this cohort, new postoperative severe HAs at last follow-up visit were found in 19% of patients. By multivariate analysis, only GON preservation (relative risk: 1.49; 95% confidence interval: 1.00-2.34; P = 0.05) and wound infection (relative risk: 2.29; 95% confidence interval: 0.91-4.25; P = 0.07) were statistically significant. By univariate analysis, positive dependent associations included GON preservation (P < .01), reconstruction of the porus with hydroxyapatite cement (P = 0.02), and wound infection (P < 0.01). Statistically significant differences in the incidence of HA after surgery were found in patients in whom the GON was preserved compared with patients in whom the GON was divided (P = 0.035). Postoperative debilitating HAs are a common complication after SOC. Although these HAs are probably multifactorial in nature, preservation of the GON during SOC is independently associated with postoperative debilitating HAs.


Cluster of Malassezia furfur pulmonary infections in infants in a neonatal intensive-care unit.
Between 23 and 27 July 1987, three infants at one hospital developed severe bronchopneumonia associated with respiratory failure, thrombocytopenia, and leukocytosis. Two infants died; at postmortem examination, Malassezia furfur was identified in their lung tissues. M. furfur was isolated from cultures of blood, urine, and stool samples from the infant who survived. All documented M. furfur infections occurred in infants with a birth weight of less than 1,000 g; the attack rate was 42.9% (three of seven infants). A case-control study comparing the three cases and nine infants randomly selected from infants in the neonatal intensive care unit during the outbreak showed the following variables to be significantly associated with case-infants: younger gestational age (less than 26 weeks), hyaline membrane disease, duration of ventilation, duration of antimicrobial therapy, and the presence of a Broviac catheter. In a second case-control study, in which case-infants were compared with birth weight-matched controls, only the duration of antimicrobial therapy was significantly associated with case-infants. A point prevalence culture survey showed that 2 of 10 infants and 2 of 11 personnel were colonized with M. furfur. This cluster suggests that M. furfur can be transmitted from an infected or colonized infant to other infants. Infection control practices should be aimed at (i) identifying high-risk infants and (ii) reemphasizing the importance of hand washing.


Improved statistical evaluation of group differences in connectomes by screening-filtering strategy with application to study maturation of brain connections between childhood and adolescence.
Detecting local differences between groups of connectomes is a great challenge in neuroimaging, because the large number of tests that have to be performed and the impact on multiplicity correction. Any available information should be exploited to increase the power of detecting true between-group effects. We present an adaptive strategy that exploits the data structure and the prior information concerning positive dependence between nodes and connections, without relying on strong assumptions. As a first step, we decompose the brain network, i.e., the connectome, into subnetworks and we apply a screening at the subnetwork level. The subnetworks are defined either according to prior knowledge or by applying a data driven algorithm. Given the results of the screening step, a filtering is performed to seek real differences at the node/connection level. The proposed strategy could be used to strongly control either the family-wise error rate or the false discovery rate. We show by means of different simulations the benefit of the proposed strategy, and we present a real application of comparing connectomes of preschool children and adolescents.


A Novel Prototype Neonatal Resuscitator That Controls Tidal Volume and Ventilation Rate: A Comparative Study of Mask Ventilation in a Newborn Manikin.
The objective of this randomized controlled manikin trial was to examine tidal volume (VT) delivery and ventilation rate during mask positive pressure ventilation (PPV) with five different devices, including a volume-controlled prototype Next Step™ device for neonatal resuscitation. We hypothesized that VT and rate would be closest to target with the Next Step™. Twenty-five Neonatal Resuscitation Program providers provided mask PPV to a newborn manikin (simulated weight 1 kg) in a randomized order with a self-inflating bag (SIB), a disposable T-piece, a non-disposable T-piece, a stand-alone resuscitation system T-piece, and the Next Step™. All T-pieces used a peak inflation pressure of 20 cmH2O and a positive end-expiratory pressure of 5 cmH2O. The participants were instructed to deliver a 5 mL/kg VT (rate 40-60/min) for 1 min with each device and each of three test lungs with increasing compliance of 0.5, 1.0, and 2.0 mL/cmH2O. VT and ventilation rate were compared between devices and compliance levels (linear mixed model). All devices, except the Next Step™ delivered a too high VT, up to sixfold the target at the 2.0-mL/cmH2O compliance. The Next Step™ VT was 26% lower than the target in the low compliance. The ventilation rate was within target with the Next Step™ and SIB, and slightly lower with the T-pieces. In conclusion, routinely used newborn resuscitators over delivered VT, whereas the Next Step™ under delivered in the low compliant test lung. The SIB had higher VT and rate than the T-pieces. More research is needed on volume-controlled delivery room ventilation.


Laryngeal structure and function in dogs with cough.
OBJECTIVE To investigate the prevalence and type of laryngeal abnormalities in dogs examined because of cough that did not have signs of upper airway disease and to compare the prevalence of those abnormalities among dogs with various respiratory tract diseases. DESIGN Prospective study. ANIMALS 138 dogs with cough that did not have signs of upper airway disease. PROCEDURES The study was conducted between July 2001 and October 2014 and included dogs examined for cough that had laryngoscopic and bronchoscopic examinations performed by 1 examiner. Laryngeal hyperemia and swelling were recorded, and laryngeal function was assessed before and after doxapram stimulation when indicated. Results were compared among dogs on the basis of cough duration (acute [< 2 weeks], subacute [2 weeks to 2 months], and chronic [> 2 months]) and disease diagnosed (inflammatory airway disease, airway collapse, lower respiratory tract infection, and eosinophilic bronchopneumopathy). RESULTS Laryngeal hyperemia was detected in 73 of 134 (54%) dogs with cough of subacute or chronic duration, and its prevalence did not vary significantly among dogs with various diseases. Thirteen dogs had laryngeal paresis, and 13 dogs had laryngeal paralysis; dysphonia (n = 2) and stridor (1) were uncommon findings in those dogs. The prevalence of laryngeal dysfunction (paresis or paralysis) did not differ significantly among diseases. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that 26 of 138 (19%) dogs examined because of cough alone had laryngeal dysfunction, which suggested that a complete laryngoscopic examination should be included in the diagnostic evaluation of dogs with cough.


A clinical audit of the management of acute asthmatic attacks in adults and children presenting to an emergency department.
To compare the guidelines in the University Hospital of the West Indies (UHWI) acute asthma management protocol with actual practice in the Accident and Emergency Department. A prospective docket audit was done of all consecutive medical records of patients, presenting with a diagnosed acute asthmatic attack between June 1 and September 30, 2010, to the emergency department of the UHWI. A convenient sample was used. The audit tool used was created from the UHWI protocol for the emergency management of asthma in adults and children, as well as the British Adult Asthma Audit Tool. The audit tool assessed three main sections: initial assessment, initial management, and discharge considerations. Data were coded and entered in Microsoft Excel 2007 and statistical analyses conducted using Stata version 10. Management patterns were compared to the actual protocol and then discussed. A total of 15 864 patients were seen during the study period. Of these, a total of 293 patients were seen for a presentation of acute asthma. More females (57.3%) than males were seen, with the mean age of 33.53 years. Only 31% of patients were given a severity assessment of mild, moderate, or severe. Peak expiratory flow rate (PEFR) was attempted and recorded in 62%, but only 18.1% of patients had both pre and post PEFR done. Only 4.4% of patients were administered nebulizations within the suggested time frame. Positively, 94.2% of patients were given a prescription for inhaled corticosteroids and bronchodilators to continue post-discharge. Acute asthma management still remains an area of medical practice that continues to have long-standing difficulties. Failure to assess and document the severity of asthma attacks along with the under-utilization of PEFR was noted.


The argon beam coagulator provides rapid hemostasis of experimental hepatic and splenic hemorrhage in anticoagulated dogs.
The argon beam coagulator (ABC) delivers radiofrequency electrical energy to tissue across a jet of argon gas, providing noncontact, monopolar, electrothermal hemostasis. This study compared the efficacy of the ABC with conventional techniques for control of traumatic hepatic and splenic hemorrhage. Standardized lacerations were made to the liver and spleen of 6 heparinized dogs. Control of bleeding was attempted with the ABC (150 W), the Nd:YAG laser (90 W, noncontact), horizontal mattress suture, microcrystalline collagen, and regenerated cellulose. If bleeding had not been controlled within 3 minutes, coagulation was attempted with the ABC in order to prevent exsanguination. Tissue from both the liver and spleen was assessed histologically for damage induced by the ABC. Delayed injury and early healing after ABC coagulation was studied in six additional dogs killed 1 and 3 weeks postoperatively. The ABC stopped bleeding from 25/25 hepatic lacerations in 48 +/- 8 seconds (mean +/- SEM) and from 18/18 splenic lacerations in 28 +/- 3 seconds. The Nd:YAG laser, mattress sutures, and topical hemostatic agents failed to control bleeding in 14 of 15 applications after 3 minutes. The ABC successfully salvaged all failures in less than 1 minute. The depth of splenic and hepatic thermal injury with the ABC ranged from 2 to 7 mm and was proportional to the duration of application. Postoperatively wound healing progressed normally without bleeding or infection at the coagulation site. The ABC appears to be a excellent instrument for achieving hemostasis in solid organ injury, and may be especially valuable in managing patients with coagulation deficits.


Effect of fasting on coagulation factors in patients who undergo major abdominal surgery.
Major abdominal surgery without preoperative adequate oral intake with some cephalosporins may result in vitamin K deficiency and bleeding tendency. The aim of this study is to clarify the effect of preoperative fasting on postoperative coagulation factors. We prospectively examined 16 patients who underwent major abdominal surgery. Patients were divided into a preoperative fast group (Group F, n = 7, mean period of preoperative fasting 8.7 days) and a control group (Group C, n = 9). We did not administer vitamin K and initiated feeding after the seventh postoperative day. In Group C, prothrombin time (PT) and Factors II, VII, IX, and X levels were decreased after the surgery to within normal limits. In Group F, the PT and Factors II, VII, and X levels were decreased after the surgery. Abnormal lower levels of PT and Factors II, VII, and X were seen in 67, 33, 67, and 67 per cent of patients after the surgery, respectively. Factors VII and X levels were higher than in Group C by the third postoperative day. The protein induced by vitamin K absence or antagonist-II levels in Group F were increased at all postoperative points. Clinicians should realize that preoperative fasting for as little as 1 week can induce precoagulopathy, resulting in postoperative coagulopathy after major surgery.


Central Europe temperature constrained by speleothem fluid inclusion water isotopes over the past 14,000 years.
The reasons for the early Holocene temperature discrepancy between northern hemispheric model simulations and paleoclimate reconstructions-known as the Holocene temperature conundrum-remain unclear. Using hydrogen isotopes of fluid inclusion water extracted from stalagmites from the Milandre Cave in Switzerland, we established a mid-latitude European mean annual temperature reconstruction for the past 14,000 years. Our Milandre Cave fluid inclusion temperature record (MC-FIT) resembles Greenland and Mediterranean sea surface temperature trends but differs from recent reconstructions obtained from biogenic proxies and climate models. The water isotopes are further synchronized with tropical precipitation records, stressing the Northern Hemisphere signature. Our results support the existence of a European Holocene Thermal Maximum and data-model temperature discrepancies. Moreover, data-data comparison reveals a significant latitudinal temperature gradient within Europe. Last, the MC-FIT record suggests that seasonal biases in the proxies are not the primary cause of the Holocene temperature conundrum.


MEG covariance difference analysis: a method to extract target source activities by using task and control measurements.
A method is proposed for extracting target dipolesource activities from two sets of evoked magnetoencephalographic (MEG) data, one measured using task stimuli and the other using control stimuli. The difference matrix between the two covariance matrices obtained from these two measurements is calculated, and a procedure similar to the MEG-multiple signal classification (MUSIC) algorithm is applied to this difference matrix to extract the target dipole-source configuration. This configuration corresponds to the source-configuration difference between the two measurements. Computer simulation verified the validity of the proposed method. The method was applied to actual evoked-field data obtained from simulated task-and-control experiments. In these measurements, a combination of auditory and somatosensory stimuli was used as the task stimulus and the somatosensory stimulus alone was used as the control stimulus. The proposed covariance difference analysis successfully extracted the target auditory source and eliminated the disturbance from the somatosensory sources.


Preparedness of Lithuanian general practitioners to provide mental healthcare services: a cross-sectional survey.
A large unmet need for mental healthcare in Lithuania is partially attributable to a lack of primary care providers with skills in this area. The aim of this study was to assess general practitioners' (GPs) experience in mental healthcare and their perceptions about how to increase their involvement in the field. In this cross-sectional study, a 41-item questionnaire was distributed to a random sample of 797 Lithuanian GPs in order to investigate current practices in their provision of mental healthcare as well as their suggestions for the improvement of mental healthcare services in primary care. The response rate was 52.2%. Three-quarters of the GPs agreed that they feel responsible for the management of mental health problems, but only 8.8% of them agreed that "My knowledge in mental healthcare is sufficient". Psychiatrists were identified as the mental healthcare team specialists with whom 32% of the respondents discuss the management of their patients with a mental disorder. Collaboration with psychologists and social workers was almost threefold lower (11.6% and 12.5%). Capacity-building of GPs was found to be among the most promising initiatives to improve mental health services in primary care. Other strategies mentioned were policy level and managerial measures as well as strengthening the teamwork approach in mental healthcare. This study found a low self-reported competence of GPs in mental healthcare and low collaboration among GPs and other specialists in providing mental healthcare. For the situation to improve in the country, these findings point to a need for strategies to improve GPs' expertise and teamwork in mental healthcare.


Bioavailable curcumin formulations: A review of pharmacokinetic studies in healthy volunteers.
Curcumin is a widely studied natural compound which has shown tremendous in vitro therapeutic potential. Despite that, the clinical efficacy of the native curcumin is weak due to its low bioavailability and high metabolism in the gastrointestinal tract. During the last decade, researchers have come up with different formulations with a focus on improving the bioavailability of curcumin. As a result, a significant number of bioavailable curcumin-based formulations were introduced with the varying range of enhanced bioavailability. The purpose of this review is to collate the published clinical studies of curcumin products with improved bioavailability over conventional (unformulated) curcumin. Based on the literature search, 11 curcumin formulations with available human bioavailability and pharmacokinetics data were included in this review. Further, the data on clinical study design, analytical method, pharmacokinetic parameters and other relevant details of each formulation were extracted. Based on a review of these studies, it is evident that better bioavailability of formulated curcumin products is mostly attributed to improved solubility, stability, and possibly low first-pass metabolism. The review hopes to provide a quick reference guide for anyone looking information on these bioavailable curcumin formulations. Based on the published reports, NovaSol® (185), CurcuWin® (136) and LongVida® (100) exhibited over 100-fold higher bioavailability relative to reference unformulated curcumin. Suggested mechanisms accounting for improved bioavailability of the formulations and details on the bioanalysis methods are also discussed.


Amurensin G induces autophagy and attenuates cellular toxicities in a rotenone model of Parkinson's disease.
Although Parkinson's disease is a common neurodegenerative disorder its cause is still unknown. Recently, several reports showed that inducers of autophagy attenuate cellular toxicities in Parkinson's disease models. In this report we screened HEK293 cells that stably express GFP-LC3, a marker of autophagy, for autophagy inducers and identified amurensin G, a compound isolated from the wild grape (Vitis amurensis). Amurensin G treatment induced punctate cytoplasmic expression of GFP-LC3 and increased the expression level of endogenous LC3-II. Incubation of human dopaminergic SH-SY5Y cells with amurensin G attenuated the cellular toxicities of rotenone in a model of Parkinson's disease. Amurensin G inhibited rotenone-induced apoptosis and interfered with rotenone-induced G2/M cell cycle arrest. In addition, knockdown of beclin1, a regulator of autophagy, abolished the effect of amurensin G. These data collectively indicate that amurensin G attenuates cellular toxicities through the induction of autophagy.


[Nasal carriage of Streptococcus pneumoniae in elderly subjects according to vaccination status].
S pneumoniae is the main cause of community-acquired pneumonia in the elderly, group that concentrates 95% of deaths. To assess the prevalence of nasal carriage of S pneumoniae in institutionalized elderly patients. One hundred eighteen institutionalized subjects aged over 60 years (65 males) were enrolled. Since they were also participating in a controlled protocol related to the immunogenicity of an anti-pneumococcal vaccine, our investigation was also blind and randomized. According to randomization, they received pneumococcal or tetanic vaccine. Nasal swab cultures were taken at the beginning of the trial and two months after vaccination. According to recommended methods, we identified S pneumoniae, the serotypes and their antimicrobial susceptibility. In the first nasal sample, 16% of subjects were positive for S pneumoniae. The second sample was positive in 12%. Of the 33 isolated serotypes, 9.1% demonstrated intermediate resistance to penicillin and 3.3% were resistant to chloramphenicol. The study demonstrated a greater percentage of colonized patients than in the general population. The isolated serotypes are the same that cause invasive diseases in this age group, according to data of the Institute of Public Health of Chile. There were no differences in the percentage of colonization between subjects vaccinated against S pneumoniae and control groups, after two months of follow up. Isolated strains had a low resistance to penicillin. High level resistance was not observed.


Ixazomib for the treatment of multiple myeloma.
Proteasome inhibitors (PIs) are among the backbones of multiple myeloma (MM) treatment; however, their long-term use can be limited by parenteral administration and treatment-related toxicities. Ixazomib, the first oral PI to enter the clinic, is approved around the world, in combination with lenalidomide and dexamethasone, for the treatment of patients with MM who have received at least one prior therapy. Areas covered: This review summarizes the clinical data leading to approval of ixazomib; its pharmacology, efficacy, and safety. Building on the data in relapsed/refractory MM (RRMM), it also reviews the available clinical trial data for ixazomib across the MM treatment algorithm in newly diagnosed MM, RRMM, and as maintenance therapy, and looks ahead to ongoing clinical trials and the expanding role of ixazomib in these indications. Expert opinion: Ixazomib is an efficacious and well-tolerated addition to the treatment armamentarium for RRMM, with benefit as a long-term, continuous therapy for all patients, including 'poor prognosis' patients, such as those with advanced stage disease, high-risk cytogenetic abnormalities, and elderly and frail patients. Data from ongoing clinical studies are expected to expand the role of ixazomib across the MM treatment algorithm and in a broader range of combination regimens.


Murine scent mark microbial communities are genetically determined.
Scent marking in mice allows males to communicate information such as territory ownership, male competitive ability and current reproductive, nutritional, social and health status. It has been suggested that female mice eavesdrop on these olfactory cues, using them as a means of selecting mates with dissimilar major histocompatibility complex (MHC) genes, known as H2 in mice. The mechanisms underpinning MHC-dependent olfactory communication remain unresolved. Using congenic mouse strains and molecular methods we explore the involvement of the microbial communities, a known source of odourants, in scent marks to test the hypothesis that the microbial communities and hence the olfactory signals are genetically determined. Here we show that the indigenous microbial community of murine scent marks is genetically determined. Both background genotype and H2 haplotype influence the community structure of the scent mark flora, removing the possibility that community composition is solely orchestrated by the MHC. Qualitative and quantitative components of the bacterial community associated with MHC haplotype and background genotype were identified. The analyses confirm that the four groups of congenic mice tested are distinguishable on basis of the microbiology of their scent marks alone, strengthening the role of microorganisms in the development of MHC-dependent odours.


Long-term effects of baroreflex function after stenting in patients with carotid artery stenosis.
Baroreflex sensitivity is recognized for its prognostic relevance to cardio-vascular and cerebro-vascular risks. However, little is known about the long-term outcome of baroreflex function in patients with carotid stenosis undergoing carotid stenting. Heart rate variability and cardio-vascular autonomic function, including baroreflex sensitivity, were examined using non-invasive methods in 22 adult patients who underwent carotid stenting. They were compared with the normal control group with 22 sex- and age-matched normal volunteers and the risk control group with 10 adult patients with severe stenosis or even total occlusion of the carotid artery without stenting. The groups of patients with stenting and risk controls had significantly reduced valsalva ratio and baroreflex sensitivity measured by the valsalva method compared to normal controls. However, there was no significant difference between patients with stenting and risk controls. There was significant decrease in heart rate response to deep breathing and to head-up tilt in patients with carotid stenting compared to normal controls. Other parameters of cardio-vascular autonomic function showed no difference among the three groups. Reduced baroreceptor function in patients with carotid stenting may be due to underlying diseases rather than the stenting itself. There was no short-term parasympathetic hyperactivity after the stenting, suggesting that the effect is transient rather than permanent.


Body mass index and family histories in type II diabetic propositi and preliminary observations on the transmission of diabetes in polygamous families.
We studied family histories of diabetes mellitus in the first-degree relatives of 356 type II diabetic propositi in whose families monogamy is practiced. Positive family histories were noted in 32% of the propositi: parental 20%, sibling 14%, and offspring 0.6%. In 11 pedigrees with conjugal diabetic parents, 33% (18/55) of their offspring were diabetic. Paternal influence was significantly higher than maternal influence (43 of 62 vs. 19 of 62, Z = 2.86, p < 0.01). The presence or absence of sibling history did not depend on the body mass index in the propositi. We also studied pedigrees of 10 propositi in whose paternal families polygamy is practiced. In these families also a trend toward greater paternal influence was noted. We conclude that (1) a family history of diabetes is present in one-third of diabetic propositi, (2) paternal influence is stronger than maternal influence in the transmission of diabetes, (3) sibling history for diabetes has no relation to the body mass index of the propositi, (4) prevalence of diabetes is higher in the offspring of conjugal diabetic parents, and (5) studies in polygamous families are a new approach that may help to quantify the genetic load transmitted from a parent when there is heterogeneity in the spouses.


OpenSpace: A System for Astrographics.
Human knowledge about the cosmos is rapidly increasing as instruments and simulations are generating new data supporting the formation of theory and understanding of the vastness and complexity of the universe. OpenSpace is a software system that takes on the mission of providing an integrated view of all these sources of data and supports interactive exploration of the known universe from the millimeter scale showing instruments on spacecrafts to billions of light years when visualizing the early universe. The ambition is to support research in astronomy and space exploration, science communication at museums and in planetariums as well as bringing exploratory astrographics to the class room. There is a multitude of challenges that need to be met in reaching this goal such as the data variety, multiple spatio-temporal scales, collaboration capabilities, etc. Furthermore, the system has to be flexible and modular to enable rapid prototyping and inclusion of new research results or space mission data and thereby shorten the time from discovery to dissemination. To support the different use cases the system has to be hardware agnostic and support a range of platforms and interaction paradigms. In this paper we describe how OpenSpace meets these challenges in an open source effort that is paving the path for the next generation of interactive astrographics.


Abnormal Bolus Reflux Is Associated With Poor Pulmonary Outcome in Patients With Idiopathic Pulmonary Fibrosis.
Gastroesophageal reflux (GER) is postulated to play a role in idiopathic pulmonary fibrosis (IPF). However, the value of objective GER measures in predicting IPF disease progression is unclear. We aim to evaluate the association between objective GER measures on multichannel intraluminal impedance and pH (MII-pH) testing and development of poor pulmonary outcomes within 1 year in prelung transplant IPF patients. This was a retrospective cohort study of adults with IPF who underwent pre-lung transplant evaluation with MII-pH off proton pump inhibitors (PPI) at a tertiary care center from June 2008 to November 2015. Patients were followed for 1 year from time of MII-pH for poor pulmonary outcomes, defined by hospitalization for respiratory exacerbation or death. Univariate, multivariate and time-to-event analyses were performed to assess associations between baseline GER parameters on MII-pH and poor outcomes. Eighty-four subjects (mean age 61.1 years, 64.3% male) were included. Subjects with increased bolus exposure time (BET) had a higher incidence of 1-year poor pulmonary outcome vs normal BET (45.7% vs 15.2%, P = 0.006). Increased BET remained an independent predictor of poor outcome after controlling for age, gender, body mass index, smoking, lung disease severity, and PPI use (OR, 4.18; P = 0.030). Increased BET was also predictive of decreased time to poor pulmonary outcome (hazard ratio [HR], 4.88; P = 0.007). Subgroup analyses showed that increased BET remained independently associated with time to pulmonary hospitalization (HR, 4.00; P = 0.020), with a trend for 1-year mortality (HR, 2.19; P = 0.380). Increased BET on MII-pH is an independent predictor of poor pulmonary outcome over 1 year in IPF patients.


Mitigation of the replication of SARS-CoV-2 by nitric oxide in vitro.
The ongoing SARS-CoV-2 pandemic is a global public health emergency posing a high burden on nations' health care systems and economies. Despite the great effort put in the development of vaccines and specific treatments, no prophylaxis or effective therapeutics are currently available. Nitric oxide (NO) is a broad-spectrum antimicrobial and a potent vasodilator that has proved to be effective in reducing SARS-CoV replication and hypoxia in patients with severe acute respiratory syndrome. Given the potential of NO as treatment for SARS-CoV-2 infection, we have evaluated the in vitro antiviral effect of NO on SARS-CoV-2 replication. The NO-donor S-nitroso-N-acetylpenicillamine (SNAP) had a dose dependent inhibitory effect on SARS-CoV-2 replication, while the non S-nitrosated NAP was not active, as expected. Although the viral replication was not completely abolished (at 200 μM and 400 μM), SNAP delayed or completely prevented the development of viral cytopathic effect in treated cells, and the observed protective effect correlated with the level of inhibition of the viral replication. The capacity of the NO released from SNAP to covalently bind and inhibit SARS-CoV-2 3CL recombinant protease in vitro was also tested. The observed reduction in SARS-CoV-2 protease activity was consistent with S-nitrosation of the enzyme active site cysteine.


DNA metallization: principles, methods, structures, and applications.
DNA metallization has witnessed tremendous growth and development, from the initial simple synthesis aimed at manufacturing conductive metal nanowires to the current fabrication of various nanostructures for applications in areas as diverse as nanolithography, energy conversion and storage, catalysis, sensing, and biomedical engineering. To this, our aim here was to present a comprehensive review to summarize the research activities on DNA metallization that have appeared since the concept was first proposed in 1998. We start with a brief presentation of the basic knowledge of DNA and its unique advantages in the template-directed growth of metal nanomaterials, followed by providing a systematic summary of the various synthetic methods developed to date to deposit metals on DNA scaffolds. Then, the leverage of DNAs with different sequences, conformations, and structures for tuning the synthesis of feature-rich metal nanostructures is discussed. Afterwards, the discussion is divided around the applications of these metal nanomaterials in the fields mentioned above, wherein the key role DNA metallization plays in enabling high performance is emphasized. Finally, the current status and some future prospects and challenges in this field are summarized. As such, this review would be of great interest to promote the further development of DNA metallization by attracting researchers from various communities, including chemistry, biology, physiology, material science, and nanotechnology as well as other disciplines.


Effects of controlled whole-body vibration training in improving fall risk factors among individuals with multiple sclerosis: A pilot study.
The purpose of this study was to systematically examine the effect of an 8-week controlled whole-body vibration training on improving fall risk factors and the bone mineral density among people with multiple sclerosis (PwMS). This study adopted a single group pre-test-post-test design. Twenty-five PwMS (50.3 years SD 14.1) received vibration training on a side-alternating vibration platform. Each training session was repeated three times every week for 8 weeks. Prior to and following the 8-week training course, a battery of fall risk factors were evaluated: the body balance, functional mobility, muscle strength, range of motion, and fear of falling. Bone density at both calcanei was also assessed. Twenty-two participants completed the study. Compared with pre-test, almost all fall risk factors and the bone density measurement were significantly improved at post-test, with moderate to large effect sizes varying between 0.571 and 1.007. The 8-week vibration training was well accepted by PwMS and improved their fall risk factors. The important findings of this study were that vibration training may increase the range of motion of ankle joints on the sagittal plane, lower the fear of falling, and improve bone density. IMPLICATIONS FOR REHABILITATION An 8-week vibration training course could be well-accepted by people with multiple sclerosis (MS). Vibration training improves the risk factors of falls in people living with MS. Vibration training could be a promising rehabilitation intervention in individuals with MS.


Translation, cross-cultural adaptation and reliability of the german version of the dizziness handicap inventory.
To translate the Dizziness Handicap Inventory into German (DHI-G) and investigate reliability, assess the association between selected items of the University of California Los Angeles Dizziness Questionnaire and the DHI-G, and compare the scores of patients and healthy participants. Cross-sectional design. Tertiary center for vertigo, dizziness, or balance disorders. One hundred forty-one patients with vertigo, dizziness, and unsteadiness associated with a vestibular disorder, with a mean age (standard deviation) of 51.5 (13.2) years, and 52 healthy individuals participated. Fourteen patients participated in the cognitive debriefing; 127 patients completed the questionnaires once or twice within 1 week. The DHI-G assesses disability caused by dizziness and unsteadiness; the items of the University of California Los Angeles Dizziness Questionnaire assess dizziness and impact on everyday activities. Internal consistency was estimated using Cronbach alpha, reproducibility by calculating Bland-Altman limits of agreement and intraclass correlation coefficients. Associations were estimated by Spearman correlation coefficients. Patients filled out the DHI-G without problem and found that their self-perceived disabilities were mostly included. Cronbach alpha values for the DHI-G and the functional, physical, and emotional subscales were 0.90, 0.80, 0.71, and 0.82, respectively. The limits of agreement were +/-12.4 points for the total scale (maximum, 100 points). Intraclass correlation coefficients ranged from 0.90 to 0.95. The DHI-G correlated moderately with the question assessing functional disability (0.56) and fairly with the questions quantifying dizziness (0.43, 0.35). The DHI-G discriminated significantly between healthy participants and patients. The DHI-G demonstrated good reliability and is recommended as a measure of disability in patients with dizziness and unsteadiness.


Structural rationale for the affinity of pico- and femtomolar transition state analogues of Escherichia coli 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase.
Immucillin and DADMe-Immucillin inhibitors are tight binding transition state mimics of purine nucleoside phosphorylases (PNP). 5'-Methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) is proposed to form a similar transition state structure as PNP. The companion paper describes modifications of the Immucillin and DADMe-Immucillin inhibitors to better match transition state features of MTAN and have led to 5'-thio aromatic substitutions that extend the inhibition constants to the femtomolar range (Singh, V., Evans, G. B., Lenz, D. H., Mason, J., Clinch, K., Mee, S., Painter, G. F., Tyler, P. C., Furneaux, R. H., Lee, J. E., Howell, P. L., and Schramm, V. L. (2005) J. Biol. Chem. 280, 18265-18273). 5'-Methylthio-Immucillin A (MT-ImmA) and 5'-methylthio-DADMe-Immucillin A (MT-DADMe-ImmA) exhibit slow-onset inhibition with K(i)(*) of 77 and 2 pm, respectively, and were selected for structural analysis as the parent compounds of each class of transition state analogue. The crystal structures of Escherichia coli MTAN complexed with MT-ImmA and MT-DADMe-ImmA were determined to 2.2 A resolution and compared with the existing MTAN inhibitor complexes. These MTAN-transition state complexes are among the tightest binding enzyme-ligand complexes ever described and analysis of their mode of binding provides extraordinary insight into the structural basis for their affinity. The MTAN-MT-ImmA complex reveals the presence of a new ion pair between the 4'-iminoribitol atom and the nucleophilic water (WAT3) that captures key features of the transition state. Similarly, in the MTAN-MT-DADMe-ImmA complex a favorable hydrogen bond or ion pair interaction between the cationic 1'-pyrrolidine atom and WAT3 is crucial for tight affinity. Distance analysis of the nucleophile and leaving group show that MT-ImmA is a mimic of an early transition state, while MT-DADMe-ImmA is a better mimic of the highly dissociated transition state of E. coli MTAN.


Effects of Active and Passive Recovery on Muscle Oxygenation and Swimming Performance.
To compare the effectiveness of 3 recovery protocols on muscle oxygenation, blood lactate, and subsequent performance during a 200-m repeated swim session. Twelve collegte swimmers completed 3 sessions of 2 consecutive 200-m front-crawl trials separated by 1 of 3 recovery protocols: a 15-minute active recovery (AR), a 15-minute passive recovery (PR), and a combination of 5-minute AR and 10-minute PR (CR) in a counterbalanced design. Tissue saturation index at biceps femoris, blood lactate concentration, arterial oxygen saturation, and heart rate were measured at rest, immediately after the trial, and at 5, 10, and 15 minutes of recovery. Two-way analysis of variance (recovery × time) with repeated measures was used to determine measurement variables. A level of significance was set at P < .05. No significant changes in swimming time were observed between trials (AR: 156.79 [4.09] vs 157.79 [4.23] s, CR: 156.50 [4.89] vs 155.55 [4.86] s, PR: 156.54 [4.70] vs 156.30 [4.52] s) across recovery conditions. Interestingly, tissue saturation index rapidly declined immediately after a 200-m swim and then gradually returned to baseline, with a greater value observed during CR compared with AR and PR after 15-minute recovery (P = .04). These changes were concomitant with significant reductions in blood lactate and heart rate during the recovery period (P = .00). The CR in the present study was more effective in enhancing muscle reoxygenation after a 200-m swim compared with AR and PR, albeit its beneficial effect on subsequent performance warrants further investigation.


R vs. S fluoroproline ring substitution: trans/cis effects on the formation of b2 ions in gas-phase peptide fragmentation.
The b2 structures of model systems Xxx-Flp-Ala (Flp = 4R-fluoroproline) and Xxx-flp-Ala (flp = 4S-fluoroproline) (where Xxx is Val or Tyr) were studied by action IRMPD spectroscopy. Proline ring substitutions influence the trans/cis isomerization of the precursor ion, resulting in different b2 fragment ion structures by collision induced dissociation. Vibrational spectra of the b2 ions of Val-Flp and Val-flp exhibit highly intense bands at ~1970 cm(-1), revealing that the dominant ion in each case is an oxazolone. The major difference between the spectra of b2 ions for R vs. S fluoroproline is a collection of peaks at 1690 and 1750 cm(-1), characteristic of a diketopiperazine structure, which were only present in the 4S-fluoroproline (flp) cases. This suggests only one b2 ion structure (oxazolone) is being formed for Flp-containing peptides, whereas flp-containing peptides produce a mixture of a dominant oxazolone with a lower population of diketopiperazine. In solution, Flp is known to possess a higher trans percentage in the N-terminally adjacent peptide bond, with flp inducing a greater proportion of the cis conformation. The diketopiperazine formation observed here correlates directly with the Ktrans/cis trend previously shown in solution, highlighting that the trans/cis isomerization likelihood for proline residues modified in the 4(th) position is retained in the gas-phase.


Leukemia inhibitory factor as an intrapituitary mediator of ACTH secretion.
In the normal anterior pituitary, intercellular interactions are important for the expression of hormones including adrenocorticotropin (ACTH). Leukemia inhibitory factor (LIF) is secreted by anterior pituitary cells and stimulates both basal and corticotropin-releasing hormone (CRH)-stimulated ACTH secretion in AtT20 cells. To determine the effects of LIF on normal pituitary cells, we measured the effects of LIF and an immunoneutralizing antiserum against LIF on ACTH secretion by cultured sheep anterior pituitary cells. In intact populations of anterior pituitary cells, LIF (10 nM) stimulated ACTH secretion (from 0.30 +/- 0.06 to 0.77 +/- 0.01 ng/well per 3 h) and antiserum to LIF (by itself) had no effect (0.29 +/- 0.05 ng/well per 3 h). In marked contrast, following pharmacological elimination of CRH-target cells, a condition known to disinhibit ACTH secretion, basal ACTH secretion was elevated (0.74 +/- 0.13 ng/well per 3 h); LIF produced no further stimulation (0.73 +/- 0.22 ng/well per 3 h) but immunoneutralization of LIF significantly reduced secretion to 0.50 +/- 0.10 ng/well per 3 h. Medium, conditioned by exposure to CRH-target-depleted cultures of anterior pituitary cells, increased net ACTH secretion (from 0.29 +/- 0.03 to 6.54 +/- 0.71 ng/well per 3 h), when added as a challenge to naive, cultured anterior pituitary cells. Inclusion of antiserum to LIF significantly attenuated (5.29 +/- 0.62 ng/well per 3 h) this response. The presence in and secretion of LIF by normal individual pituitary cells was detected using immunocytochemical methods. Seven to 8% of all cells stained positively for LIF, with 66 +/- 11% of those secreting detectable amounts of LIF under unstimulated conditions. LIF colocalized with TSH and LH in pituitary cells. Taken together, these data suggest that LIF can stimulate ACTH secretion by normal anterior pituitary cells, and potentially plays a role as an intrapituitary stimulator of ACTH secretion under certain conditions.


Maternal hypothyroxinemia impairs spatial learning and synaptic nature and function in the offspring.
Neurological deficits in the offspring caused by human maternal hypothyroxinemia are thought to be irreversible. To understand the mechanism responsible for these neurological alterations, we induced maternal hypothyroxinemia in pregnant rats. Behavior and synapse function were evaluated in the offspring of thyroid hormone-deficient rats. Our data indicate that, when compared with controls, hypothyroxinemic mothers bear litters that, in adulthood, show prolonged latencies during the learning process in the water maze test. Impaired learning capacity caused by hypothyroxinemia was consistent with cellular and molecular alterations, including: 1) lack of increase of phosphorylated c-fos on the second day of the water maze test; 2) impaired induction of long-term potentiation in response to theta-burst stimulation to the Schaffer collateral pathway in the area 1 of the hippocampus Ammon's horn stratum radiatum, despite normal responses for input/output experiments; 3) increase of postsynaptic density protein 95 (PSD-95), N-methyl-D-aspartic acid receptor subunit 1, and tyrosine receptor kinase B levels in brain extracts; and 4) significant increase of PSD-95 at the PSDs and failure of this molecule to colocalize with N-methyl-D-aspartic acid receptor subunit 1, as it was shown by control rats. Our findings suggest that maternal hypothyroxinemia is a harmful condition for the offspring that can affect key molecular components for synaptic function and spatial learning.


Coexistence of different serotypes of dengue virus.
We formulate a non-linear system of differential equations that models the dynamics of dengue fever. This disease is produced by any of the four serotypes of dengue arbovirus. Each serotype produces permanent immunity to it, but only a certain degree of cross-immunity to heterologous serotypes. In our model we consider the relation between two serotypes. Our interest is to analyze the factors that allow the invasion and persistence of different serotypes in the human population. Analysis of the model reveals the existence of four equilibrium points, which belong to the region of biological interest. One of the equilibrium points corresponds to the disease-free state, the other three equilibria correspond to the two states where just one serotype is present, and the state where both serotypes coexist, respectively. We discuss conditions for the asymptotic stability of equilibria, supported by analytical and numerical methods. We find that coexistence of both serotypes is possible for a large range of parameters.


Effect of diurnal variation, CYP2B6 genotype and age on the pharmacokinetics of nevirapine in African children.
To characterize the effects of CYP2B6 polymorphisms, diurnal variation and demographic factors on nevirapine pharmacokinetics in African children. Non-linear mixed-effects modelling conducted in NONMEM 7.3 described nevirapine plasma concentration-time data from 414 children aged 0.3-15 years. Nevirapine pharmacokinetics was best described using a one-compartment disposition model with elimination through a well-stirred liver model accounting for a first-pass effect and transit-compartment absorption. Intrinsic clearance was affected by diurnal variation (characterized using a cosine function with peak amplitude 29% at 12 noon) and CYP2B6 metabolizer status [extensive metabolizer (EM) 516GG|983TT, reference; intermediate metabolizer (IM) 516GT|983TT or 516GG|983TC, 17% lower; slow metabolizer (SM) 516TT|983TT or 516GT|983TC, 50% lower; ultra-slow metabolizer (USM) 516GG|983CC, 68% lower]. Age was found to affect pre-hepatic bioavailability: 31.7% lower at birth and increasing exponentially. Median (90% CI) evening Cmin values in the different metabolizer groups were 5.01 (3.01-7.47), 6.55 (3.65-13.32), 11.59 (5.44-22.71) and 12.32 (12.32-27.25) mg/L, respectively. Evening Cmin values were <3 mg/L in 43% of EM weighing <6 kg and 26% of IM weighing <6 kg, while 73% of SM and 88% of USM in all weight-bands had evening Cmin values >8 mg/L. Cmin was not markedly affected by administration time, but was altered by unequal splitting of the daily dose. Diurnal variation does not greatly affect nevirapine exposure. However, when daily doses cannot be split equally, the larger dose should be given in the morning. To achieve homogeneous exposures, nevirapine doses for SM and USM should be reduced by 50%, and children weighing <6 kg with EM or IM metabolizer status should receive the same dose as children weighing 6-10 kg.


Underage drinking: prevalence and correlates of risky drinking measures among youth aged 12-20.
Underage drinking and its effects have been researched extensively. However, no study to date has examined how the levels of drinking that have been defined as risky for adults might relate to youth who have a heightened physiological vulnerability to alcohol. To examine a range of drinking measures that go beyond common measures of youth alcohol use to gain a more detailed understanding of the nature of underage drinking and its associated correlates and outcomes. Analyzing data from a 2013 nationally representative US survey, we examined a variety of measures of alcohol use among 24,445 youth (weighted N = 381,155,562), the demographic groups most likely to have reported drinking in these ways, and associations between these measures of drinking and a number of adverse outcomes. On all measures of potentially risky drinking, including meeting diagnostic criteria for an alcohol use disorder, underage drinkers exceeded the rates found for adults. Independent of sex, race, and age, youth who reported drinking in ways that exceeded guidelines set for adults had increased odds of meeting diagnostic criteria for an alcohol, tobacco, or other drug use disorder, and of reporting a number of health problems. The high rates at which youth report engaging in a range of risky drinking behaviors suggest a need for a more nuanced approach to substance use and mental health screening and interventions in clinical practice. The findings also underscore the need to address apparent misconceptions about what constitutes unhealthy or unsafe alcohol use among youth.


Enhanced abdominal aortic aneurysm formation in thrombin-activatable procarboxypeptidase B-deficient mice.
To determine whether procarboxypeptidase B (pCPB)(-/-) mice are susceptible to accelerated abdominal aortic aneurysm (AAA) development secondary to unregulated OPN-mediated mural inflammation in the absence of CPB inhibition. Thrombin/thrombomodulin cleaves thrombin-activatable pCPB or thrombin-activatable fibrinolysis inhibitor, activating CPB, which inhibits the generation of plasmin and inactivates proinflammatory mediators (complement C5a and thrombin-cleaved osteopontin [OPN]). Apolipoprotein E(-/-)OPN(-/-) mice are protected from experimental AAA formation. Murine AAAs were created via intra-aortic porcine pancreatic elastase (PPE) infusion. Increased mortality secondary to AAA rupture was observed in pCPB(-/-) mice at the standard PPE dose. At reduced doses of PPE, pCPB(-/-) mice developed larger AAAs than wild-type controls (1.01+/-0.27 versus 0.68+/-0.05 mm; P=0.02 [mean+/-SD]). C5(-/-) and OPN(-/-) mice were not protected against AAA development. Treatment with tranexamic acid inhibited plasmin generation and abrogated enhanced AAA progression in pCPB(-/-) mice. This study establishes the role of CPB in experimental AAA disease, indicating that CPB has a broad anti-inflammatory role in vivo. Enhanced AAA formation in the PPE model is the result of increased plasmin generation, not unregulated C5a- or OPN-mediated mural inflammation.


Factors associated with trial recruitment, preferences, and treatments received were elucidated in a comprehensive cohort study.
Recruitment to pragmatic trials is often difficult, and little is known about factors associated with key participation and treatment decisions. These were explored in the Prostate cancer testing and Treatment (ProtecT) study. Baseline sociodemographic, patient-reported outcome, clinical history, and prostate cancer biopsy data were collected for all patients eligible to take part in the ProtecT trial, in a comprehensive cohort design. Men who rejected randomization specified a preferred option and were followed up identically to the randomized cohort. Factors associated with participation decisions, patient preferences, and reasons for changing treatment were explored. Of 2,664 men with clinically localized prostate cancer, 997 (37%) rejected randomization. Their treatment preferences and subsequent treatment choices/changes in both randomized and treatment choice cohorts were strongly associated with prostate cancer risk features: toward active monitoring for low-risk disease and toward radical options with higher risk prostate cancer. Among many factors measured, only a small number of weak associations were found for occupation groups and some patient symptoms. Similar percentages changed from the random allocation and initially stated preference. The comprehensive cohort design provided new insights into trial recruitment and participation decisions. Opportunities to improve recruitment by supporting recruiters with equipoise and patient preferences were identified.


Translating research into practice: case study of a community-based dementia caregiver intervention.
One of the most devastating impacts of Alzheimer's disease and related dementias is the toll on caregivers. Evidence from randomized clinical trials has demonstrated the effectiveness of providing psychosocial interventions for caregivers to lessen their burden. However, the implementation of such interventions in community settings has proved challenging. This case study describes outcomes of the implementation of an evidence-based intervention in a multisite program in Minnesota. Consistent with the original randomized clinical trial of the intervention, assessments of this program showed decreased depression and distress among caregivers. Participating in a greater number of caregiver counseling sessions was also associated with longer time to nursing home placement for the person with dementia. Some of the challenges in the community setting included having caregivers complete the full six counseling sessions and acquiring complete outcome data. Given the challenges faced in the community setting, web-based training for providers may be a cost-effective way to realize the maximum benefits of the intervention for vulnerable adults with dementia and their families.


You eat what you are: personality-dependent filial cannibalism in a fish with paternal care.
Many animal parents invest heavily to ensure offspring survival, yet some eventually consume some or all of their very own young. This so-called filial cannibalism is known from a wide range of taxa, but its adaptive benefit remains largely unclear. The extent to which parents cannibalize their broods varies substantially not only between species, but also between individuals, indicating that intrinsic behavioral differences, or animal personalities, might constitute a relevant proximate trigger for filial cannibalism. Using a marine fish with extensive paternal care, the common goby (Pomatoschistus microps), we investigated the influence of animal personality on filial cannibalism by assessing (1) behavioral consistency across a breeding and a nonbreeding context; (2) correlations between different breeding (egg fanning; filial cannibalism) and nonbreeding (activity) behaviors, and, in a separate experiment; (3) whether previously established personality scores affect filial cannibalism levels. We found consistent individual differences in activity across contexts. Partial filial cannibalism was independent of egg fanning but correlated strongly with activity, where active males cannibalized more eggs than less active males. This pattern was strong initially but vanished as the breeding season progressed. The incidence of whole clutch filial cannibalism increased with activity and clutch size. Our findings indicate that filial cannibalism cannot generally be adjusted independently of male personality and is thus phenotypically less plastic than typically assumed. The present work stresses the multidimensional interaction between animal personality, individual plasticity and the environment in shaping filial cannibalism.


Preoperative laryngoscopy in thyroid surgery: Do patients' subjective voice complaints matter?
Although routine preoperative laryngoscopy has been standard practice for many thyroid surgeons, there is recent literature that supports selective laryngoscopy. We hypothesize that patients' preoperative voice complaints do not correlate well with abnormalities seen on preoperative laryngoscopy. A retrospective chart review of a 3-year, single-surgeon experience was performed. Records of patients undergoing thyroid surgery were reviewed for patient voice complaints, prior neck surgery, surgeon-documented voice quality, and results of laryngoscopy. Of 464 patients, 6% had abnormal laryngoscopy findings, including 11 cord paralyses (2%). Preoperatively, 39% of patients had voice complaints, but only 10% had a corresponding abnormality on laryngoscopy. Only 4% of patients had a surgeon-documented voice abnormality with 72% corresponding abnormalities on laryngoscopy, including 8 cord paralyses. When eliminating patient voice complaints and using only history of prior neck surgery and surgeon-documented voice abnormality as criteria for preoperative laryngoscopy, only 1 cord paralysis is missed and sensitivity (91%) and specificity (86%) were high. Also, when compared with routine laryngoscopy, 84% fewer laryngoscopies are performed. When using patients' voice complaints as criteria for preoperative laryngoscopy, the yield is low. We recommend using surgeon-documented voice abnormalities and history of prior neck surgery as criteria for preoperative laryngoscopy.