Effect of parental training in managing the behavioral problems of early childhood.
To examine the effect of parental training on disturbed behavior of early childhood cases presented to the pediatricians. The patients who reported in pediatric OPD of the Himalayan Institute of Medical Sciences, Dehradun, with complaints of low learning, poor memory, vertigo, speech problem, stress, headache, depression, adjustment problems, aggression, and hostile behavior were included in the study. Children aged 3 through 6 (N = 60), were screened through PBQ (Preschool Behavior Questionnaire), DST (developmental screening Test), and Vineland Social Maturity Scale (VSMS). Children included in the study had an average range of developmental quotient 85-90 (mean DQ = 87.5). Range of social quotient was 40-45 (mean SQ = 42.5). Twenty four fortnightly sessions of 'parental training' using the model of 'Mindful Parenting' were conducted. Single group t test method was applied in order to see the difference in mean of pre and post assessment of PBQ. After concluding parental training (after 24 sessions), mean difference of total disturbed behavior was found to be significant (t value: 5.31 > .05) Similarly, the mean difference of hostile/aggressive behavior (t value: 10.2 > .05), anxious behavior (t value: 18.5 > .05), and hyperactive/distractible behavior (t value: 1.97 > .05) were found to be significant. These results provide some evidence in favor of parental training in managing behavioral problems occurring in early childhood. Instead of putting the child immediately on medication, parents can get training and prepare a plan to understand and make a change in child's behavior leading to better health.


Provision and uptake of routine antenatal services: a qualitative evidence synthesis.
Antenatal care (ANC) is a core component of maternity care. However, both quality of care provision and rates of attendance vary widely between and within countries. Qualitative research can assess factors underlying variation, including acceptability, feasibility, and the values and beliefs that frame provision and uptake of ANC programmes.This synthesis links to the Cochrane Reviews of the effectiveness of different antenatal models of care. It was designed to inform the World Health Organization guidelines for a positive pregnancy experience and to provide insights for the design and implementation of improved antenatal care in the future. To identify, appraise, and synthesise qualitative studies exploring:· Women's views and experiences of attending ANC; and factors influencing the uptake of ANC arising from women's accounts;· Healthcare providers' views and experiences of providing ANC; and factors influencing the provision of ANC arising from the accounts of healthcare providers. To find primary studies we searched MEDLINE, Ovid; Embase, Ovid; CINAHL, EbscoHost; PsycINFO, EbscoHost; AMED, EbscoHost; LILACS, VHL; and African Journals Online (AJOL) from January 2000 to February 2019. We handsearched reference lists of included papers and checked the contents pages of 50 relevant journals through Zetoc alerts received during the searching phase. We included studies that used qualitative methodology and that met our quality threshold; that explored the views and experiences of routine ANC among healthy, pregnant and postnatal women or among healthcare providers offering this care, including doctors, midwives, nurses, lay health workers and traditional birth attendants; and that took place in any setting where ANC was provided.We excluded studies of ANC programmes designed for women with specific complications. We also excluded studies of programmes that focused solely on antenatal education. Two authors undertook data extraction, logged study characteristics, and assessed study quality. We used meta-ethnographic and Framework techniques to code and categorise study data. We developed findings from the data and presented these in a 'Summary of Qualitative Findings' (SoQF) table. We assessed confidence in each finding using GRADE-CERQual. We used these findings to generate higher-level explanatory thematic domains. We then developed two lines of argument syntheses, one from service user data, and one from healthcare provider data. In addition, we mapped the findings to relevant Cochrane effectiveness reviews to assess how far review authors had taken account of behavioural and organisational factors in the design and implementation of the interventions they tested. We also translated the findings into logic models to explain full, partial and no uptake of ANC, using the theory of planned behaviour. We include 85 studies in our synthesis. Forty-six studies explored the views and experiences of healthy pregnant or postnatal women, 17 studies explored the views and experiences of healthcare providers and 22 studies incorporated the views of both women and healthcare providers. The studies took place in 41 countries, including eight high-income countries, 18 middle-income countries and 15 low-income countries, in rural, urban and semi-urban locations. We developed 52 findings in total and organised these into three thematic domains: socio-cultural context (11 findings, five moderate- or high-confidence); service design and provision (24 findings, 15 moderate- or high-confidence); and what matters to women and staff (17 findings, 11 moderate- or high-confidence) The third domain was sub-divided into two conceptual areas; personalised supportive care, and information and safety. We also developed two lines of argument, using high- or moderate-confidence findings:For women, initial or continued use of ANC depends on a perception that doing so will be a positive experience. This is a result of the provision of good-quality local services that are not dependent on the payment of informal fees and that include continuity of care that is authentically personalised, kind, caring, supportive, culturally sensitive, flexible, and respectful of women's need for privacy, and that allow staff to take the time needed to provide relevant support, information and clinical safety for the woman and the baby, as and when they need it. Women's perceptions of the value of ANC depend on their general beliefs about pregnancy as a healthy or a risky state, and on their reaction to being pregnant, as well as on local socio-cultural norms relating to the advantages or otherwise of antenatal care for healthy pregnancies, and for those with complications. Whether they continue to use ANC or not depends on their experience of ANC design and provision when they access it for the first time.The capacity of healthcare providers to deliver the kind of high-quality, relationship-based, locally accessible ANC that is likely to facilitate access by women depends on the provision of sufficient resources and staffing as well as the time to provide flexible personalised, private appointments that are not overloaded with organisational tasks. Such provision also depends on organisational norms and values that overtly value kind, caring staff who make effective, culturally-appropriate links with local communities, who respect women's belief that pregnancy is usually a normal life event, but who can recognise and respond to complications when they arise. Healthcare providers also require sufficient training and education to do their job well, as well as an adequate salary, so that they do not need to demand extra informal funds from women and families, to supplement their income, or to fund essential supplies. This review has identified key barriers and facilitators to the uptake (or not) of ANC services by pregnant women, and in the provision (or not) of good-quality ANC by healthcare providers. It complements existing effectiveness reviews of models of ANC provision and adds essential insights into why a particular type of ANC provided in specific local contexts may or may not be acceptable, accessible, or valued by some pregnant women and their families/communities. Those providing and funding services should consider the three thematic domains identified by the review as a basis for service development and improvement. Such developments should include pregnant and postnatal women, community members and other relevant stakeholders.


O-GlcNAcase overexpression reverses coronary endothelial cell dysfunction in type 1 diabetic mice.
Cardiovascular disease is the primary cause of morbidity and mortality in diabetes, and endothelial dysfunction is commonly seen in these patients. Increased O-linked N-acetylglucosamine (O-GlcNAc) protein modification is one of the central pathogenic features of diabetes. Modification of proteins by O-GlcNAc (O-GlcNAcylation) is regulated by two key enzymes: β-N-acetylglucosaminidase [O-GlcNAcase (OGA)], which catalyzes the reduction of protein O-GlcNAcylation, and O-GlcNAc transferase (OGT), which induces O-GlcNAcylation. However, it is not known whether reducing O-GlcNAcylation can improve endothelial dysfunction in diabetes. To examine the effect of endothelium-specific OGA overexpression on protein O-GlcNAcylation and coronary endothelial function in diabetic mice, we generated tetracycline-inducible, endothelium-specific OGA transgenic mice, and induced OGA by doxycycline administration in streptozotocin-induced type 1 diabetic mice. OGA protein expression was significantly decreased in mouse coronary endothelial cells (MCECs) isolated from diabetic mice compared with control MCECs, whereas OGT protein level was markedly increased. The level of protein O-GlcNAcylation was increased in diabetic compared with control mice, and OGA overexpression significantly decreased the level of protein O-GlcNAcylation in MCECs from diabetic mice. Capillary density in the left ventricle and endothelium-dependent relaxation in coronary arteries were significantly decreased in diabetes, while OGA overexpression increased capillary density to the control level and restored endothelium-dependent relaxation without changing endothelium-independent relaxation. We found that connexin 40 could be the potential target of O-GlcNAcylation that regulates the endothelial functions in diabetes. These data suggest that OGA overexpression in endothelial cells improves endothelial function and may have a beneficial effect on coronary vascular complications in diabetes.


Building International Genomics Collaboration for Global Health Security.
Genome science and technologies are transforming life sciences globally in many ways and becoming a highly desirable area for international collaboration to strengthen global health. The Genome Science Program at the Los Alamos National Laboratory is leveraging a long history of expertise in genomics research to assist multiple partner nations in advancing their genomics and bioinformatics capabilities. The capability development objectives focus on providing a molecular genomics-based scientific approach for pathogen detection, characterization, and biosurveillance applications. The general approaches include introduction of basic principles in genomics technologies, training on laboratory methodologies and bioinformatic analysis of resulting data, procurement, and installation of next-generation sequencing instruments, establishing bioinformatics software capabilities, and exploring collaborative applications of the genomics capabilities in public health. Genome centers have been established with public health and research institutions in the Republic of Georgia, Kingdom of Jordan, Uganda, and Gabon; broader collaborations in genomics applications have also been developed with research institutions in many other countries.


An iterative approach for generating statistically realistic populations of households.
Many different simulation frameworks, in different topics, need to treat realistic datasets to initialize and calibrate the system. A precise reproduction of initial states is extremely important to obtain reliable forecast from the model. This paper proposes an algorithm to create an artificial population where individuals are described by their age, and are gathered in households respecting a variety of statistical constraints (distribution of household types, sizes, age of household head, difference of age between partners and among parents and children). Such a population is often the initial state of microsimulation or (agent) individual-based models. To get a realistic distribution of households is often very important, because this distribution has an impact on the demographic evolution. Usual techniques from microsimulation approach cross different sources of aggregated data for generating individuals. In our case the number of combinations of different households (types, sizes, age of participants) makes it computationally difficult to use directly such methods. Hence we developed a specific algorithm to make the problem more easily tractable. We generate the populations of two pilot municipalities in Auvergne region (France) to illustrate the approach. The generated populations show a good agreement with the available statistical datasets (not used for the generation) and are obtained in a reasonable computational time.


Understanding face familiarity.
It has been known for many years that identifying familiar faces is much easier than identifying unfamiliar faces, and that this familiar face advantage persists across a range of tasks. However, attempts to understand face familiarity have mostly used a binary contrast between 'familiar' and 'unfamiliar' faces, with no attempt to incorporate the vast range of familiarity we all experience. From family members to casual acquaintances and from personal to media exposure, familiarity is a more complex categorisation than is usually acknowledged. Here we model levels of familiarity using a generic statistical analysis (PCA combined with LDA) computed over some four thousand naturally occurring images that include a large variation in the numbers of images for each known person. Using a strong test of performance with entirely novel, untrained everyday images, we show that such a model can simulate widely documented effects of familiarity in face recognition and face matching, and offers a natural account of the internal feature advantage for familiar faces. Furthermore, as with human viewers, the benefits of familiarity seem to accrue from being able to extract consistent information across different photos of the same face. We argue that face familiarity is best understood as reflecting increasingly robust statistical descriptions of idiosyncratic within-person variability. Understanding how faces become familiar appears to rely on both bottom-up statistical image descriptions (modelled here with PCA), and top-down processes that cohere superficially different images of the same person (modelled here with LDA).


LAF1, a MYB transcription activator for phytochrome A signaling.
The photoreceptor phytochrome (phy) A has a well-defined role in regulating gene expression in response to specific light signals. Here, we describe a new Arabidopsis mutant, laf1 (long after far-red light 1) that has an elongated hypocotyl specifically under far-red light. Gene expression studies showed that laf1 has reduced responsiveness to continuous far-red light but retains wild-type responses to other light wavelengths. As far-red light is only perceived by phyA, our results suggest that LAF1 is specifically involved in phyA signal transduction. Further analyses revealed that laf1 is affected in a subset of phyA-dependent responses and the phenotype is more severe at low far-red fluence rates. LAF1 encodes a nuclear protein with strong homology with the R2R3-MYB family of DNA-binding proteins. Experiments using yeast cells identified a transactivation domain in the C-terminal portion of the protein. LAF1 is constitutively targeted to the nucleus by signals in its N-terminal portion, and the full-length protein accumulates in distinct nuclear speckles. This accumulation in speckles is abolished by a point mutation in a lysine residue (K258R), which might serve as a modification site by a small ubiquitin-like protein (SUMO).


Assessing the choice of National Health Insurance Fund contracted outpatient facilities in Kenya: A qualitative study.
To assess National Health Insurance Fund (NHIF) members' level of understanding, experiences, and factors influencing their choice of NHIF-contracted outpatient facilities in Kenya. We conducted a cross-sectional qualitative study with NHIF members in two purposefully selected counties (Nyeri and Makueni counties) in Kenya. We collected data through 15 focus group discussions with NHIF members. Data were analysed using a framework analysis approach. Urban-based NHIF members had a good understanding of the NHIF-contracted outpatient facility selection process and the approaches for choosing and changing providers, unlike their rural counterparts. While NHIF members were required to choose a provider before accessing care, the number of available alternative facilities was perceived to be inadequate. Finally, NHIF members identified seven factors they considered important when choosing an NHIF-contracted outpatient provider. Of these factors, the availability of drugs, distance from the household to the facility and waiting time at the facility until consultation were considered the most important. There is a need for the NHIF to prioritise awareness-raising approaches tailored to rural settings. Further, there is a need for the NHIF to contract more providers to both spur competition among providers and provide alternatives for members to choose from. Besides, NHIF members revealed the important factors they consider when selecting outpatient facilities. Consequently, NHIF should leverage the preferred factors when contracting healthcare providers. Similarly, healthcare providers should enhance the availability of drugs, reduce waiting times whilst improving their staff's attitudes which would improve user satisfaction and the quality of care provided.


Anterior and posterior optic nerve head blood flow in nonhuman primate experimental glaucoma model measured by laser speckle imaging technique and microsphere method.
To characterize optic nerve head (ONH) blood flow (BF) changes in nonhuman primate experimental glaucoma (EG) using laser speckle flowgraphy (LSFG) and the microsphere method and to evaluate the correlation between the two methods. EG was induced in one eye each of 9 rhesus macaques by laser treatment to the trabecular meshwork. Prior to lasering and following onset of intraocular pressure (IOP) elevation, retinal never fiber layer thickness (RNFLT) and ONH BF were measured biweekly by spectral-domain optical coherence tomography and LSFG, respectively, until RNFLT loss was approximately 40% in the EG eye. Final BF was measured by LSFG and by the microsphere method in the anterior ONH (MS-BF(ANT)), posterior ONH (MS-BF(POST)), and peripapillary retina (MS-BF(PP)). Baseline RNFLT and LSFG-BF showed no difference between the two eyes (P = 0.69 and P = 0.43, respectively, paired t-test). Mean (± SD) IOP was 30 ± 6 mm Hg in EG eyes and 13 ± 2 mm Hg in control eyes (P < 0.001). EG eye RNFLT and LSFG-BF were reduced by 42 ± 16% (P < 0.0001) and 22 ± 13% (P = 0.003), respectively, at the final time point. EG eye MS-BF(ANT), MS-BF(POST), and MS-BF(PP) were reduced by 41 ± 17% (P < 0.001), 22 ± 34% (P = 0.06), and 30 ± 12% (P = 0.001), respectively, compared with the control eyes. Interocular ONH LSFG-BF differences significantly correlated to that measured by the microsphere method (R(2) = 0.87, P < 0.001). Chronic IOP elevation causes significant ONH BF decreases in the EG model. The high correlation between the BF reduction measured by LSFG and the microsphere method provides evidence that the LSFG is capable of assaying BF for a critical deep ONH region.


Resident participation in index laparoscopic general surgical cases: impact of the learning environment on surgical outcomes.
The NSQIP database enables measurement of postoperative outcomes across a spectrum of practice settings. This allows for observations about potential effects of resident participation in surgical care during training. We queried the NSQIP database for 6 index laparoscopic surgical procedures performed during 2005-2008. Selected procedures require varying skill level (eg, appendectomy, cholecystectomy, gastric bypass, fundoplication, colectomy, and inguinal hernia), and 79,720 cases were identified. Preoperative, operative, and postoperative outcomes for each procedure were tabulated. Operative and postoperative outcomes assessed included operative time, hospital length of stay, mortality, morbidity, and return to the operating room. Initial analysis compared cases done with a resident present with cases done without residents. Subset analysis was done to determine possible differences in outcomes based on the level of resident participating, divided into Junior (PGY1-2), Senior (PGY3-5), or Fellow (PGY>5). Groups were scrutinized for both clinical and statistical differences. Preoperative characteristics were similar between groups. Operative times were 20% to 47% longer with resident participation, with bigger differences seen in more basic procedures. Mortality and return to the operating room were not clinically different between the groups. Morbidity rates were higher in all procedures with resident participation. More senior residents were associated with longer operative times, without adverse impact on outcomes. Resident participation increases operative times for laparoscopic surgery considerably. Morbidity is statistically higher with resident participation but differences are unlikely to be clinically significant. Resident participation is a surrogate for the learning environment. These findings provide impetus for additional development of training techniques that occur outside the operating room.


Enhancement of Th1-biased protective immunity against avian influenza H9N2 virus via oral co-administration of attenuated Salmonella enterica serovar Typhimurium expressing chicken interferon-α and interleukin-18 along with an inactivated vaccine.
Control of currently circulating re-assorted low-pathogenicity avian influenza (LPAI) H9N2 is a major concern for both animal and human health. Thus, an improved LPAI H9N2 vaccination strategy is needed to induce complete immunity in chickens against LPAI H9N2 virus strains. Cytokines play a crucial role in mounting both the type and extent of an immune response generated following infection with a pathogen or after vaccination. To improve the efficacy of inactivated LPAI H9N2 vaccine, attenuated Salmonella enterica serovar Typhimurium was used for oral co-administration of chicken interferon-α (chIFN-α) and chicken interleukin-18 (chIL-18) as natural immunomodulators. Oral co-administration of S. enterica serovar Typhimurium expressing chIFN-α and chIL-18, prior to vaccination with inactivated AI H9N2 vaccine, modulated the immune response of chickens against the vaccine antigen through enhanced humoral and Th1-biased cell-mediated immunity, compared to chickens that received single administration of S. enterica serovar Typhimurium expressing either chIFN-α or chIL-18. To further test the protective efficacy of this improved vaccination regimen, immunized chickens were intra-tracheally challenged with a high dose of LPAI H9N2 virus. Combined administration of S. enterica serovar Typhimurium expressing chIFN-α and chIL-18 showed markedly enhanced protection compared to single administration of the construct, as determined by mortality, clinical severity, and feed and water intake. This enhancement of protective immunity was further confirmed by reduced rectal shedding and replication of AIV H9N2 in different tissues of challenged chickens. Our results indicate the value of combined administration of chIFN-α and chIL-18 using a Salmonella vaccine strain to generate an effective immunization strategy in chickens against LPAI H9N2.


Pit and fissure sealants versus fluoride varnishes for preventing dental decay in children and adolescents.
The majority of the detected increment in dental caries among children and adolescents is confined to pit and fissure surfaces of first molars. The objective of this study was to compare the effectiveness of pit and fissure sealants with fluoride varnishes in the prevention of dental decay on occlusal surfaces. The Cochrane Oral Health Group's Trials Register, CENTRAL, MEDLINE, EMBASE and 10 other databases were searched to November 2009. There were no language or publication restrictions. Random or quasi-random allocation study design; sealants versus fluoride varnish or sealants and fluoride varnish combination versus fluoride varnish alone; and subjects under 20 years of age. The primary outcome of interest was the increment in the numbers of carious occlusal surfaces of permanent premolars and molars. Two review authors independently screened search results, extracted data and assessed the risk of bias of trials. Risk ratios (RR) were calculated for differences between intervention and control groups and in split-mouth studies for differences of paired tooth surfaces being carious or not. No data could be combined or meta-analyses undertaken due to the clinical and methodological diversity between study designs. Four studies were eligible for inclusion in the review. Results of one split-mouth study at low risk of bias and one cluster randomised study at moderate/high risk of bias revealed the effectiveness of pit and fissure sealants to be statistically significantly higher than an application of fluoride varnish every 6 months in preventing occlusal decays of first molars at 23 months (with a RR of 0.74, 95% confidence interval (CI) 0.58 to 0.95); and at 4 years and 9 years (with a RR of 0.42, 95% CI 0.21 to 0.84 and RR of 0.48, 95% CI 0.29 to 0.79, respectively). One small parallel group study at moderate/high risk of bias failed to find a difference between sealants and fluoride varnishes. Further, one split-mouth study at low risk of bias with 24 months of follow-up found significantly more caries on the fluoride varnished tooth surfaces, compared to sealed plus fluoride varnished surfaces, with a RR of 0.36 (95% CI 0.21 to 0.61). There was some evidence on the superiority of pit and fissure sealants over fluoride varnish application in the prevention of occlusal decays. However, current scarce data limit recommendations on whether to apply pit and fissure sealants or fluoride varnishes on occlusal surfaces.


Analysis of the interaction of induction regimens with p-glycoprotein expression in patients with acute myeloid leukaemia: results from the MRC AML15 trial.
Retrospective analyses in non-randomised cohorts suggest that regimens containing fludarabine/Ara C and/or idarubicin/ara C may be more effective than daunorubicin/AraC (DA)-containing regimens in cases of acute myeloid leukaemia (AML) overexpressing p-glycoprotein (Pgp). We prospectively measured Pgp protein and function by flow cytometry in CD45-gated blasts from 434 AML15 trial patients randomised to remission induction therapy with two courses of FLAG-Ida or DA±etoposide (DA/ADE). In all, 34% were positive for Pgp protein and 38% for function. Pgp protein-positive cases had a higher incidence of resistant disease (14% vs 5%), adjusted odds ratio 2.67 (1.14-6.24). There was a trend towards a higher cumulative incidence of relapse at 5 years for Pgp-positive cases (46% vs 55%), adjusted hazard ratio 1.42 (0.98-2.07) (P=0.06). For patients treated with FLAG-Ida, the complete remission (CR) rate was 86% for both Pgp-positive and Pgp-negative patients. In patients treated with DA/ADE, 78% of Pgp-positive and 90% of Pgp-negative cases achieved CR (P=0.06). In analyses of overall survival, there was no interaction between treatment received and Pgp expression. Data for Pgp function followed similar trends. Our data suggest that FLAG-Ida may improve the remission rate for Pgp-positive AML, but the malignant clone is reduced rather than eradicated such that the relapse rate remains high in Pgp-positive patients.


Focus on the success of others leads to selfish behavior.
It has often been argued that the spectacular cognitive capacities of humans are the result of selection for the ability to gather, process, and use information about other people. Recent studies show that humans strongly and consistently differ in what type of social information they are interested in. Although some individuals mainly attend to what the majority is doing (frequency-based learning), others focus on the success that their peers achieve with their behavior (success-based learning). Here, we show that such differences in social learning have important consequences for the outcome of social interactions. We report on a decision-making experiment in which individuals were first classified as frequency- and success-based learners and subsequently grouped according to their learning strategy. When confronted with a social dilemma situation, groups of frequency-based learners cooperated considerably more than groups of success-based learners. A detailed analysis of the decision-making process reveals that these differences in cooperation are a direct result of the differences in information use. Our results show that individual differences in social learning strategies are crucial for understanding social behavior.


Phlorotannins from Alaskan seaweed inhibit carbolytic enzyme activity.
Global incidence of type 2 diabetes has escalated over the past few decades, necessitating a continued search for natural sources of enzyme inhibitors to offset postprandial hyperglycemia. The objective of this study was to evaluate coastal Alaskan seaweed inhibition of α-glucosidase and α-amylase, two carbolytic enzymes involved in serum glucose regulation. Of the six species initially screened, the brown seaweeds Fucus distichus and Alaria marginata possessed the strongest inhibitory effects. F. distichus fractions were potent mixed-mode inhibitors of α-glucosidase and α-amylase, with IC50 values of 0.89 and 13.9 μg/mL, respectively; significantly more efficacious than the pharmaceutical acarbose (IC50 of 112.0 and 137.8 μg/mL, respectively). The activity of F. distichus fractions was associated with phlorotannin oligomers. Normal-phase liquid chromatography-mass spectrometry (NPLC-MS) was employed to characterize individual oligomers. Accurate masses and fragmentation patterns confirmed the presence of fucophloroethol structures with degrees of polymerization from 3 to 18 monomer units. These findings suggest that coastal Alaskan seaweeds are sources of α-glucosidase and α-amylase inhibitory phlorotannins, and thus have potential to limit the release of sugar from carbohydrates and thus alleviate postprandial hyperglycemia.


CotE binds to CotC and CotU and mediates their interaction during spore coat formation in Bacillus subtilis.
CotE is a morphogenic protein that controls the assembly of the coat, the proteinaceous structure that surrounds and protects the spore of Bacillus subtilis. CotE has long been thought to interact with several outer coat components, but such interactions were hypothesized from genetic experiment results and have never been directly demonstrated. To study the interaction of CotE with other coat components, we focused our attention on CotC and CotU, two outer coat proteins known to be under CotE control and to form a heterodimer. We report here the results of pull-down experiments that provide the first direct evidence that CotE contacts other coat components. In addition, coexpression experiments demonstrate that CotE is needed and sufficient to allow formation of the CotC-CotU heterodimer in a heterologous host.


Is an aggressive surgical approach to the patient with gastric lymphoma warranted?
At the Mayo Clinic, from 1970 through 1979, 84 patients (52 males and 32 females) had abdominal exploration for primary gastric lymphoma. All patients were observed a minimum of 5 years or until death. The histologic findings for all 84 patients were reviewed. Forty-four patients had "curative resection," and 40 patients had either biopsy alone or a palliative procedure. The probability of surviving 5 years was 75% for patients after potentially curative resection and 32% for patients after biopsy and palliation (p less than 0.001). The operative mortality rate was 5% overall and 2% after potentially curative resection. Increased tumor size (p less than 0.02), increased tumor penetration (p less than 0.01), and lymph node involvement (p less than 0.02) decreased the probability of survival, whereas histologic classification did not affect survival. Radiation therapy after surgery did not significantly affect the survival rate for the entire group or the survival rate for patients who had potentially curative resection. Resectability was associated with increased patient survival--independent of other prognostic factors--when our experience was analyzed by the Cox proportional-hazards model (p less than 0.005). It was concluded that an aggressive surgical attitude in the treatment of primary gastric lymphoma is warranted. The role of radiotherapy remains in question.


The human gut microbiota and its interactive connections to diet.
The microbiota of the gastrointestinal tract plays an important role in human health. In addition to their metabolic interactions with dietary constituents, gut bacteria may also be involved in more complex host interactions, such as modulation of the immune system. Furthermore, the composition of the gut microbiota may be important in reducing the risk of contracting particular gut infections. Changes in the microbiota during an individual's lifespan are accompanied by modifications in multiple health parameters, and such observations have prompted intense scientific efforts aiming to understand the complex interactions between the microbiota and its human host, as well as how this may be influenced by diet.


Markers of Celiac Disease and Gluten Sensitivity in Children with Autism.
Gastrointestinal symptoms are a common feature in children with autism, drawing attention to a potential association with celiac disease or gluten sensitivity. However, studies to date regarding the immune response to gluten in autism and its association with celiac disease have been inconsistent. The aim of this study was to assess immune reactivity to gluten in pediatric patients diagnosed with autism according to strict criteria and to evaluate the potential link between autism and celiac disease. Study participants included children (with or without gastrointestinal symptoms) diagnosed with autism according to both the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview, Revised (ADI-R) (n = 37), their unaffected siblings (n = 27), and age-matched healthy controls (n = 76). Serum specimens were tested for antibodies to native gliadin, deamidated gliadin, and transglutaminase 2 (TG2). Affected children were genotyped for celiac disease associated HLA-DQ2 and -DQ8 alleles. Children with autism had significantly higher levels of IgG antibody to gliadin compared with unrelated healthy controls (p<0.01). The IgG levels were also higher compared to the unaffected siblings, but did not reach statistical significance. The IgG anti-gliadin antibody response was significantly greater in the autistic children with gastrointestinal symptoms in comparison to those without them (p<0.01). There was no difference in IgA response to gliadin across groups. The levels of celiac disease-specific serologic markers, i.e., antibodies to deamidated gliadin and TG2, did not differ between patients and controls. An association between increased anti-gliadin antibody and presence of HLA-DQ2 and/or -DQ8 was not observed. A subset of children with autism displays increased immune reactivity to gluten, the mechanism of which appears to be distinct from that in celiac disease. The increased anti-gliadin antibody response and its association with GI symptoms points to a potential mechanism involving immunologic and/or intestinal permeability abnormalities in affected children.


[Reef fishes community structure in 4 atolls of the San Andrés - Providencia Archipelago (Southwestern Caribbean)].
In 1994 and 1995, 131 visual censuses of reef fishes were made using the stationary sampling method in Courtown, Albuquerque, Serrana and Roncador, four atolls of the Archipelago of San Andrés and Old Providence in the Southwestern Caribbean. Fish species and their abundances were recorded in four geomorphologic zones: lagoon, windward barrier reef, windward terrace and forereef terrace. A total of 98 species were censused; the most abundant were Chromis cyanea (14%), Clepticus parra (14%) and Stegastes partitus (10%). The most abundant families were Pomacentridae (37%), Labridae (28%) and Scaridae (10%). Analysis of similarities showed that differences between zones were greater than differences between atolls, but lagoon and forereef terrace were not significantly different. Cluster and ordination analysis confirmed these results; in addition, the ordination analysis placed the groups according to depth and wave-exposure gradients, suggesting that these two physical variables were responsibles for the clustering. Differences in equitability and species richness appear also due to these variables. Inverse analysis showed in each group few characteristic species, then the differences between zones were due specially to dominance of some species. The dominant trophic categories were planktivorous and herbivorous that were significantly different between zones. In shallow zones (shallow lagoonal patch reefs) and high wave-exposed zones (winward barrier reef) dominated herbivorous fishes, while in deeper zones (terraces and deep lagoonal patch reefs) planktivorous were more abundant.


Challenges and unanswered questions for the next decade of circulating tumour cell research in lung cancer.
Since blood borne circulating tumour cells (CTCs) initially shed from the primary tumour can seed and initiate metastasis at distant sites a better understanding of the biology of CTCs and their dissemination could provide valuable information that could guide therapeutic intervention and real time monitoring of disease progression. Although CTC enumeration has provided a reliable prognostic readout for a number of cancers, including lung cancer, the precise clinical utility of CTCs remains to be established. The rarity of CTCs together with the vanishingly small amounts of nucleic acids present in a single cell as well as cell to cell heterogeneity has stimulated the development of a wide range of powerful cellular and molecular methodologies applied to CTCs. These technical developments are now enabling researchers to focus on understanding the biology of CTCs and their clinical utility as a predictive and pharmacodynamics markers. This review summarises recent advances in the field of CTC research with focus on technical and biological challenges as well the progress made towards clinical utility of characterisation of CTCs with emphasis on studies in lung cancer.


Differences between men and women in the regulation of adipose 11β-HSD1 and in its association with adiposity and insulin resistance.
This study explored sex differences in 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity and gene expression in isolated adipocytes and adipose tissue (AT), obtained via subcutaneous biopsies from non-diabetic subjects [58 M, 64 F; age 48.3 ± 15.3 years, body mass index (BMI) 27.2 ± 3.9 kg/m²]. Relationships with adiposity and insulin resistance (IR) were addressed. Males exhibited higher 11β-HSD1 activity in adipocytes than females, but there was no such difference for AT. In both men and women, adipocyte 11β-HSD1 activity correlated positively with BMI, waist circumference, % body fat, adipocyte size and with serum glucose, triglycerides and low-density lipoprotein:high-density lipoprotein (LDL:HDL) ratio. Positive correlations with insulin, HOMA-IR and haemoglobin A1c (HbA1c) and a negative correlation with HDL-cholesterol were significant only in males. Conversely, 11β-HSD1 activity in AT correlated with several markers of IR and adiposity in females but not in males, but the opposite pattern was found with respect to 11β-HSD1 mRNA expression. This study suggests that there are sex differences in 11β-HSD1 regulation and in its associations with markers of obesity and IR.


Evaluation of three sampling methods to monitor outcomes of antiretroviral treatment programmes in low- and middle-income countries.
Retention of patients on antiretroviral therapy (ART) over time is a proxy for quality of care and an outcome indicator to monitor ART programs. Using existing databases (Antiretroviral in Lower Income Countries of the International Databases to Evaluate AIDS and Médecins Sans Frontières), we evaluated three sampling approaches to simplify the generation of outcome indicators. We used individual patient data from 27 ART sites and included 27,201 ART-naive adults (≥15 years) who initiated ART in 2005. For each site, we generated two outcome indicators at 12 months, retention on ART and proportion of patients lost to follow-up (LFU), first using all patient data and then within a smaller group of patients selected using three sampling methods (random, systematic and consecutive sampling). For each method and each site, 500 samples were generated, and the average result was compared with the unsampled value. The 95% sampling distribution (SD) was expressed as the 2.5(th) and 97.5(th) percentile values from the 500 samples. Overall, retention on ART was 76.5% (range 58.9-88.6) and the proportion of patients LFU, 13.5% (range 0.8-31.9). Estimates of retention from sampling (n = 5696) were 76.5% (SD 75.4-77.7) for random, 76.5% (75.3-77.5) for systematic and 76.0% (74.1-78.2) for the consecutive method. Estimates for the proportion of patients LFU were 13.5% (12.6-14.5), 13.5% (12.6-14.3) and 14.0% (12.5-15.5), respectively. With consecutive sampling, 50% of sites had SD within ±5% of the unsampled site value. Our results suggest that random, systematic or consecutive sampling methods are feasible for monitoring ART indicators at national level. However, sampling may not produce precise estimates in some sites.


Macrophage Activation Syndrome (MAS) in a Recently Released Prisoner with Systemic Lupus Erythematosus (SLE).
BACKGROUND Systemic lupus erythematosus (SLE) has myriad manifestations that can affect any organ system in the body. Macrophage activation syndrome (MAS) is a disease of uncontrolled lymphocyte and macrophage proliferation and activation, which has various triggers, including autoimmune disorder, viral infection, and malignancy. We report here on MAS as a complication of adult SLE, a rare association in the literature, in a patient with an unknown past medical history. CASE REPORT A 38-year-old male patient presented with severe muscle weakness, diffuse abdominal cramps with vomiting and incontinence of stool, confusion, cough, and sweating increasing in severity for about 1 week. He was unable to give a coherent history and according to his family had been released from prison 3 weeks prior, having been in the corrections system for much of his adult life. The diagnosis of new-onset fulminant SLE complicated by MAS was made, noting the profound degree of bone marrow involvement, neuropsychiatric changes, and hyperferritinemia. CONCLUSIONS Many of the symptoms, signs, and laboratory findings of SLE overlap with those of MAS, and concomitant presence of both of these disease poses unique diagnostic challenges as well as extreme risk to the patient. A robust set of criteria for identifying MAS in the setting of a confounding underlying rheumatological illness does not exist in the adult population; this case illustrates the approach taken by our team to come to this diagnosis.


Cytoskeleton--plasma membrane interactions.
Proteins at the boundary between the cytoskeleton and the plasma membrane control cell shape, delimit specialized membrane domains, and stabilize attachments to other cells and to the substrate. These proteins also regulate cell locomotion and cytoplasmic responses to growth factors and other external stimuli. This diversity of cellular functions is matched by the large number of biochemical mechanisms that mediate the connections between membrane proteins and the underlying cytoskeleton, the so-called membrane skeleton. General organizational themes are beginning to emerge from examination of this biochemical diversity.


Synthesis and cell localization of self-assembled dinuclear lanthanide bioprobes.
Lanthanide bioprobes and bioconjugates are ideal luminescent stains in view of their low propensity to photobleaching, sharp emission lines and long excited state lifetimes permitting time-resolved detection for enhanced sensitivity. In this paper, we expand our previous work which demonstrated that self-assembled dinuclear triple-stranded helicates [Ln2(L(C2X))3] behave as excellent cell and tissue labels in immunocytochemical and immunohistochemical assays. The synthetic strategy of the hexadentate ditopic ligands incorporating dipicolinic acid, benzimidazole units and polyoxyethylene pendants is revisited in order to provide a more straightforward route and to give access to further functionalization of the polyoxyethylene arms by incorporating a terminal function X. Formation of the helicates [Ln2(L(C2X))3] (X=COOH, CH2OH, COEt, NH2, phthalimide) is ascertained by several experimental techniques and their stability tested against diethylenetriaminepentaacetate. Their photophysical properties (quantum yield, lifetime, radiative lifetime and sensitization efficiency) are presented and compared with those of the parent helicates [Ln2(L(C2))3]. Finally, the cellular uptake of five Eu(III) helicates is monitored by time-resolved luminescence microscopy and their localization in HeLa cells established by co-staining experiments.


Mitochondria in Health and Disease.
Mitochondria are best known as the sites for production of respiratory ATP and are essential for eukaryotic life. They have their own genome but the great majority of the mitochondrial proteins are encoded by the nuclear genome and are imported into the mitochondria. The mitochondria participate in critical central metabolic pathways and they are fully integrated into the intracellular signalling networks that regulate diverse cellular functions. It is not surprising then that mitochondrial defects or dysregulation have emerged as having key roles in ageing and in the cytopathological mechanisms underlying cancer, neurodegenerative and other diseases. This special issue contains 12 publications-nine review articles and three original research articles. They cover diverse areas of mitochondrial biology and function and how defects in these areas can lead to disease. In addition, the articles in this issue highlight how model organisms have contributed to our understanding of these processes.


Antiviral potency and functional analysis of tetherin orthologues encoded by horse and donkey.
Tetherin is an interferon-inducible host cell factor that blocks the viral particle release of the enveloped viruses. Most knowledge regarding the interaction between tetherin and viruses has been obtained using the primate lentiviral system. However, much less is known about the functional roles of tetherin on other lentiviruses. Equine infectious anemia virus (EIAV) is an important macrophage-tropic lentivirus that has been widely used as a practical model for investigating the evolution of the host-virus relationship. The host range of EIAV is reported to include all members of the Equidae family. However, EIAV has different clinical responses in horse and donkey. It's intriguing to investigate the similarities and differences between the tetherin orthologues encoded by horse and donkey. We report here that there are two equine tetherin orthologues. Compared to horse tetherin, there are three valine amino acid deletions within the transmembrane domain and three distinct mutations within the ectodomain of donkey tetherin. However, the antiviral activity of donkey tetherin was not affected by amino acid deletion or substitution. In addition, both tetherin orthologues encoded by horse and donkey are similarly sensitive to EIAV Env protein, and equally activate NF-κB signaling. Our data suggest that both tetherin orthologues encoded by horse and donkey showed similar antiviral activities and abilities to induce NF-κB signaling. In addition, the phenomenon about the differential responses of horses and donkeys to infection with EIAV was not related with the differences in the structure of the corresponding tetherin orthologues.


Regulation of life history determines lifespan of worker honey bees (Apis mellifera L.).
Life expectancy of honey bees (Apis mellifera L.) is of general interest to gerontological research because its variability among different groups of bees is one of the most striking cases of natural plasticity of aging. Worker honey bees spend their first days of adult life working in the nest, then transition to foraging and die between 4 and 8 weeks of age. Foraging is believed to be primarily responsible for the early death of workers. Three large-scale experiments were performed to quantitatively assess the importance of flight activity, chronological age, extrinsic mortality factors and foraging specialization. Forager mortality was higher than in-hive bee mortality. Most importantly however, reducing the external mortality hazards and foraging activity did not lead to the expected strong extension of life. Most of the experimental effects were attributable to an earlier transition from hive tasks to foraging. This transition is accompanied by a significant mortality peak. The age at the onset of foraging is the central variable in worker life-history and behavioral state was found more important than chronological age for honey bee aging. However, mortality risk increased with age and the negative relation between pre-foraging and foraging lifespan indicate some senescence irrespective of behavioral state. Overall, honey bee workers exhibit a logistic mortality dynamic which is mainly caused by the age-dependent transition from a low mortality pre-foraging state to a higher mortality foraging state.


Caffeic acid phenethyl ester inhibits diesel exhaust particle-induced inflammation of human middle ear epithelial cells via NOX4 inhibition.
Otitis media is one of the most common diseases in pediatric populations. Recent research on its pathogenesis has focused on air pollution. Chronic exposure to particulate air pollution is associated with the impairment of middle ear function. However, the mechanisms and the underlying inhibitory pathways, especially in the human middle ear, remain unknown. Caffeic acid phenethyl ester (CAPE) is a biologically active ingredient of propolis, a product of honeybee hives, which has anti-oxidative and anti-inflammatory activities. The aim of this study was to evaluate the inhibitory effect of CAPE on diesel exhaust particle (DEP)-induced inflammation of human middle ear epithelial cells and to determine the underlying pathway of the action of CAPE. The inflammatory damage caused by DEPs and the anti-inflammatory effects of CAPE were determined by measuring the levels of tumor necrosis factor alpha and nicotinamide adenine dinucleotide phosphate oxidase (NOX) 4 with real-time reverse transcription polymerase chain reaction and Western blot analysis. The oxidative stress induced by DEPs and the anti-oxidative effects of CAPE were directly evaluated by measuring reactive oxygen species production by use of flow cytometric analysis of 2',7'-dichlorofluorescein diacetate. The effects of CAPE were compared with those of N-acetyl-L-cysteine, which has anti-oxidative and anti-inflammatory effects. Use of CAPE significantly inhibited DEP-induced up-regulation of tumor necrosis factor alpha and NOX4 expression in a dose- and time-dependent manner. The accumulation of reactive oxygen species induced by DEPs was decreased by pretreatment with CAPE. The anti-inflammatory and anti-oxidative effects of CAPE were similar to those of N-acetyl-L-cysteine. The inflammation induced by DEP is reduced by CAPE via the inhibition of NOX4 expression. These findings suggest that CAPE might be used as a therapeutic agent against DEP-induced inflammation of human middle ear epithelial cells.


Massive recurrent hemoperitoneum with encapsulating peritonitis: another enigmatic clinical feature of endometriosis.
To describe the clinical characteristics and laparoscopic findings of a very uncommon presentation of a patient with endometriosis. Video presentation of case report (Canadian Task Force classification III). (The institutional review board of the Hospital Naval Pedro Mallo, Buenos Aires, Argentina, has ruled that approval was not required for the publication of this case report.) SETTING: Hospital. Thirty-two-year-old woman with endometriosis presenting with hemorrhagic ascites. We demonstrate the laparoscopic appearance of the peritoneal organs in the presence of massive hemoperitoneum and encapsulating peritonitis and also describe the diagnosis and management options of an uncommon clinical presentation of endometriosis. The patient is a 32-year-old woman, gravida 0, who presented with abdominal pain and ascites. Initially, she underwent exploratory laparotomy with drainage of 5 liters of ascites and excision of endometrial peritoneal implants. She then presented 4 months later with sudden worsening abdominal pain and distention, weight gain, bloating, and shortness of breath. A diagnostic laparoscopy was performed with the findings of over 10 liters of dark hemoperitoneum and diffuse pelviperitonitis with loose necrotic, easy to remove, dense peritoneal tissue. Patient was started on triptorelin acetate with great response. Resolution of the symptomatology secondary to hemorrhagic peritonitis. Clinical improvement of symptomatology of a patient with endometriosis and hemorrhagic ascites. Endometriosis can have different clinical presentations. Endometriosis should be a differential diagnosis in women of reproductive age presenting with massive hemorrhagic ascites. Hemorrhagic ascites, considered an exceedingly rare clinical course of endometriosis, represents a challenge to the surgeon who is unfamiliar with this condition. Bilateral oophorectomy is the definitive treatment, but conservative therapy is indicated for women of childbearing age. Diagnostic laparoscopy with drainage of hemoperitoneum is a feasible option to obtain a pathology-confirmed diagnosis in patients presenting with hemoperitoneum secondary to pelvic endometriosis. Awareness of this condition will prevent unnecessary aggressive resection, as is commonly performed when the condition is confused with ovarian cancer.


Serum immunoglobulin G4 and immunoglobulin G1 for distinguishing immunoglobulin G4-associated cholangitis from primary sclerosing cholangitis.
The recent addition of immunoglobulin (Ig)G4-associated cholangitis (IAC), also called IgG4-related sclerosing cholangitis (IRSC), to the spectrum of chronic cholangiopathies has created the clinical need for reliable methods to discriminate between IAC and the more common cholestatic entities, primary (PSC) and secondary sclerosing cholangitis. The current American Association for the Study of Liver Diseases practice guidelines for PSC advise on the measurement of specific Ig (sIg)G4 in PSC patients, but interpretation of elevated sIgG4 levels remains unclear. We aimed to provide an algorithm to distinguish IAC from PSC using sIgG analyses. We measured total IgG and IgG subclasses in serum samples of IAC (n = 73) and PSC (n = 310) patients, as well as in serum samples of disease controls (primary biliary cirrhosis; n = 22). sIgG4 levels were elevated above the upper limit of normal (ULN = >1.4 g/L) in 45 PSC patients (15%; 95% confidence interval [CI]: 11-19). The highest specificity and positive predictive value (PPV; 100%) for IAC were reached when applying the 4 × ULN (sIgG4 > 5.6 g/L) cutoff with a sensitivity of 42% (95% CI: 31-55). However, in patients with a sIgG4 between 1 × and 2 × ULN (n = 38/45), the PPV of sIgG4 for IAC was only 28%. In this subgroup, the sIgG4/sIgG1 ratio cutoff of 0.24 yielded a sensitivity of 80% (95% CI: 51-95), a specificity of 74% (95% CI: 57-86), a PPV of 55% (95% CI: 33-75), and a negative predictive value of 90% (95% CI: 73-97). Elevated sIgG4 (>1.4 g/L) occurred in 15% of patients with PSC. In patients with a sIgG4 >1.4 and <2.8 g/L, incorporating the IgG4/IgG1 ratio with a cutoff at 0.24 in the diagnostic algorithm significantly improved PPV and specificity. We propose a new diagnostic algorithm based on IgG4/IgG1 ratio that may be used in clinical practice to distinguish PSC from IAC.


A novel uHPLC-MS/MS method for the quantitation of AZD7451 (AZ12607092) in human plasma.
Tropomyosin-related kinases (Trk) are tyrosine kinase receptors implicated in tumor proliferation, invasion, and survival signaling across a number of tumors, making them potentially attractive targets for the treatment of cancer. AZD7451 is a potent and selective inhibitor of Trk kinases currently undergoing a Phase I dose escalation in glioblastoma multiforme at the National Cancer Institute. A key part of early clinical testing for AZD7451 involves demonstrating that pharmacokinetic half-life and clinical exposures of AZD7451 are sufficient to inhibit Trk receptors in preclinical models. To address this need, an ultra sensitive analytical method was developed to measure the AZD7451 profile in human plasma. A liquid-liquid extraction recovered >80% of AZD7451 before quantitative analysis by ultra HPLC-MS/MS. A Varian Polaris(®) C18-A column and a mass transition of m/z 383.5→340.5 (m/z 389.6→342.0 for the internal standard [(2)H6]-AZD7451) was used, and a dynamic calibration range of 0.5-1000ng/mL was established, which provided a sensitive (<8.5% deviation), and precise (<6%) quantitative assay for AZD7451. AZD7451 demonstrated stability in human plasma at room temperature for 24h (<7% change) and after extraction at 4°C for 24h (<8% change), and was stable through 4 freeze/thaw cycles (<8% change). This method was used to measure AZD7451 plasma levels in clinical samples to confirm the sensitivity at several time points following AZD7451 treatment in subjects with glioblastoma.


Dexamethasone inhibits the Nox-dependent ROS production via suppression of MKP-1-dependent MAPK pathways in activated microglia.
Nox-2 (also known as gp91phox), a subunit component of NADPH oxidases, generates reactive oxygen species (ROS). Nox-dependent ROS generation and nitric oxide (NO) release by microglia have been implicated in a variety of diseases in the central nervous system. Dexamethasone (Dex) has been shown to suppress the ROS production, NO release and inflammatory reaction of activated microglial cells. However, the underlying mechanisms remain unclear. The present study showed that the increased ROS production and NO release in activated BV-2 microglial cells by LPS were associated with increased expression of Nox-2 and iNOS. Dex suppressed the upregulation of Nox-2 and iNOS, as well as the subsequent ROS production and NO synthesis in activated BV-2 cells. This inhibition caused by Dex appeared to be mediated by upregulation of MAPK phosphatase-1 (MKP-1), which antagonizes the activity of mitogen-activated protein kinases (MAPKs). Dex induced-suppression of Nox-2 and -upregulation of MKP-1 was also evident in the activated microglia from corpus callosum of postnatal rat brains. The overexpression of MKP-1 or inhibition of MAPKs (by specific inhibitors of JNK and p38 MAPKs), were found to downregulate the expression of Nox-2 and iNOS and thereby inhibit the synthesis of ROS and NO in activated BV-2 cells. Moreover, Dex was unable to suppress the LPS-induced synthesis of ROS and NO in BV-2 cells transfected with MKP-1 siRNA. On the other hand, knockdown of Nox-2 in BV-2 cells suppressed the LPS-induced ROS production and NO release. In conclusion, it is suggested that downregulation of Nox-2 and overexpression of MKP-1 that regulate ROS and NO may form the potential therapeutic strategy for the treatment of neuroinflammation in neurodegenerative diseases.


IQ in early adulthood, socioeconomic position, and unintentional injury mortality by middle age: a cohort study of more than 1 million Swedish men.
The authors evaluated the little-examined association between intelligence (IQ) and injury mortality and, for the first known time, explored the extent to which IQ might explain established socioeconomic inequalities in injury mortality. A nationwide cohort of 1,116,442 Swedish men who underwent IQ testing at about 18 years of age was followed for mortality experience for an average of 22.6 years. In age-adjusted analyses in which IQ scores were classified into 4 groups, relative to the highest scoring category, the hazard ratio in the lowest was elevated for all injury types: poisonings (hazard ratio (HR) = 5.82, 95% confidence interval (CI): 4.25, 7.97), fire (HR = 4.39, 95% CI: 2.51, 7.77), falls (HR = 3.17, 95% CI: 2.19, 4.59), drowning (HR = 3.16, 95% CI: 1.85, 5.39), and road injury (HR = 2.17, 95% CI: 1.91, 2.47). Dose-response effects across the full IQ range were evident (P-trend < 0.001). Control for potential covariates, including socioeconomic position, had little impact on these gradients. When socioeconomic disadvantage -- indexed by parental and subject's own occupational social class -- was the exposure of interest, IQ explained a sizable portion (19%-86%) of the relation with injury mortality. These findings suggest that IQ may have an important role both in the etiology of injuries and in explaining socioeconomic inequalities in injury mortality.


Unique biochemical and mineral composition of whale ear bones.
Abstract Cetaceans are obligate aquatic mammals derived from terrestrial artiodactyls. The defining characteristic of cetaceans is a thick and dense lip (pachyosteosclerotic involucrum) of an ear bone (the tympanic). This unique feature is absent in modern terrestrial artiodactyls and is suggested to be important in underwater hearing. Here, we investigate the mineralogical and biochemical properties of the involucrum, as these may hold clues to the aquatic adaptations of cetaceans. We compared bioapatites (enamel, dentine, cementum, and skeletal bone) of cetaceans with those of terrestrial artiodactyls and pachyosteosclerotic ribs of manatees (Sirenia). We investigated organic, carbonate, and mineral composition as well as crystal size and crystallinity index. In all studied variables, bioapatites of the cetacean involucrum were intermediate in composition and structure between those of tooth enamel on the one hand and those of dentine, cementum, and skeletal bone on the other. We also studied the amino acid composition of the cetacean involucrum relative to that of other skeletal bone. The central involucrum had low glycine and hydroxyproline concentrations but high concentrations of nonessential amino acids, unlike most bone samples but similar to the tympanic of hippos and the (pachyosteosclerotic) ribs of manatees. These amino acid results are evidence of rapid bone development. We hypothesize that the mineralogical and amino acid composition of cetacean bullae differs from that of other bone because of (1) functional modifications for underwater sound reception and (2) structural adaptations related to rapid ossification.


Effects of parental relations and upbringing in troubled adolescent eating behaviors.
Family relations may constitute a risk for developing eating problems. Not enough is known about parent-child relationship quality and upbringing in food situations. Self-report data from 80 high school students (45 males) showed that females had more eating problems than males, and their problems were related both to insecure mother attachment, controlling for body/weight dissatisfaction, and to more memories of childhood food rules. Secure mother attachment was related to decreased eating problems, via increasing body/weight satisfaction. Especially the mother- daughter relationship seems to affect adolescent girls' eating habits and can either protect against or enhance the risk for eating problems.


Does doctors' experience matter in LASIK surgeries?
In this article, we use a longitudinal census of laser in situ keratomileusis (LASIK) eye surgeries collected directly from patient charts to examine the learning-by-doing hypothesis in medicine. LASIK surgery has precise measures of presurgical condition and postsurgical outcomes. Unlike other types of surgery, the impact of unobservable underlying patient conditions on outcomes is minimal. Individual learning by doing is identified through observations of surgical outcomes over time, based on the cumulative number of surgeries performed. Collective learning is identified separately, through changes in a group adjustment rule determined jointly by all the surgeons in a structured internal review process. Our unique data set overcomes some of the measurement problems in patient outcomes encountered in other studies and improves the possibility of identifying and separating the impact of learning by doing from other effects. We cannot conclude that the outcome of LASIK surgery improves as an individual surgeon's experience increases, but we find strong evidence that experience accumulated by surgeons as a group in a clinic significantly improves outcomes.


Stress Ulcer Prophylaxis.
Stress ulcer prophylaxis is commonly administered to critically ill patients for the prevention of clinically important stress-related mucosal bleeding from the upper gastrointestinal tract. Despite widespread incorporation of stress ulcer prophylaxis into practice around the world, questions are emerging about its indications and impact. This clinically focused article will review current controversies related to stress ulcer prophylaxis for critically ill adult patients, including bleeding frequency, risk factors, comparative efficacy, adverse effect profile, and overall cost-effectiveness of the available stress ulcer prophylaxis regimens. A MEDLINE search was conducted from inception through August 2015. Selected publications describing stress ulcer prophylaxis in adult patients were retrieved (original research, systematic reviews, and practice guidelines); their bibliographies were also reviewed to identify additional pertinent publications. Data from relevant publications were abstracted and summarized. The existing evidence is organized to describe the patients most likely to benefit from stress ulcer prophylaxis, review the comparative efficacy of proton pump inhibitors and histamine 2 receptor antagonists, the adverse effects of stress ulcer prophylaxis, and overall cost-effectiveness. Many stress ulcer prophylaxis recommendations are based on older studies at risk of bias, which may not be applicable to modern practice. Stress ulcer prophylaxis should be limited to patients considered to be at high risk for clinically important bleeding. When evaluating only the trials at low risk for bias, the evidence does not clearly support lower bleeding rates with proton pump inhibitors over histamine 2 receptor antagonists; however, proton pump inhibitors appear to be the dominant drug class used worldwide today. The current rate of upper gastrointestinal bleeding and the relative adverse effects of acid suppression on infectious risk may drive not only the effectiveness, but also the cost-effectiveness of stress ulcer prophylaxis today. Research is currently underway to better address these issues.


Health-care provider preferences for time-sensitive communications from public health agencies.
The Rapid Emergency Alert Communication in Health (REACH) Trial was a randomized control trial to systematically compare and evaluate the effectiveness of traditional and mobile communication modalities for public health agencies to disseminate time-sensitive information to health-care providers (HCPs). We conducted a sub-study to identify the communication channels by which HCPs preferred receiving public health alerts and advisories. Enrolled HCPs were blindly randomized into four message delivery groups to receive time-sensitive public health messages by e-mail, fax, or short message service (SMS) or to a no-message control group. Follow-up interviews were conducted 5-10 days after the message. In the final interview, additional questions were asked regarding HCP preferences for receiving public health alerts and advisories. We examined the relationship between key covariates and preferred method of receiving public health alert and advisory messages. Gender, age, provider type, and study site showed statistically significant associations with delivery method preference. Older providers were more likely than younger providers to prefer e-mail or fax, while younger providers were more likely than older providers to prefer receiving messages via SMS. There is currently no evidence-based research to guide or improve communication between public health agencies and HCPs. Understanding the preferences of providers for receiving alerts and advisories may improve the effectiveness of vital public health communications systems and, in turn, may enhance disease surveillance, aid in early detection, and improve case finding and situational awareness for public health emergencies.


Could Dissimilar Phenotypic Effects of ACTB Missense Mutations Reflect the Actin Conformational Change? Two Novel Mutations and Literature Review.
The beta-actin gene encodes 1 of 6 different actin proteins. De novo heterozygous missense mutations in ACTB have been identified in patients with Baraitser-Winter syndrome (BRWS) and also in patients with developmental disorders other than BRWS, such as deafness, dystonia, and neutrophil dysfunction. We describe 2 different novel de novo missense ACTB mutations, c.208C>G (p.Pro70Ala) and c.511C>T (p.Leu171Phe), found by trio exome sequencing analysis of 2 unrelated patients: an 8-year-old boy with a suspected BRWS and a 4-year-old girl with unclear developmental disorder. The mutated residue in the first case is situated in the actin H-loop, which is involved in actin polymerization. The mutated residue in the second case (p.Leu171Phe) is found at the actin barbed end in the W-loop, important for binding to profilin and other actin-binding molecules. While the boy presented with a typical BRWS facial appearance, the girl showed facial features not recognizable as a BRWS gestalt as well as ventricular arrhythmia, cleft palate, thrombocytopenia, and gray matter heterotopia. We reviewed previously published ACTB missense mutations and ascertained that a number of them do not cause typical BRWS. By comparing clinical and molecular data, we speculate that the phenotypic differences found in ACTB missense mutation carriers might supposedly be dependent on the conformational change of ACTB.


Lessons learned from implementing Clostridium difficile-focused antibiotic stewardship interventions.
To determine whether controlling the prescription of targeted antibiotics would translate to a measurable reduction in hospital-onset Clostridium difficile infection (CDI) rates. A multicenter before-and-after intervention comparative study. Ten medical centers in the greater New York region. Intervention group comprised of 6 facilities with early antimicrobial stewardship programs (ASPs). The 4 facilities without ASPs made up the nonintervention group. Intervention facilities identified target antibiotics using case-control studies and implemented ASP-based strategies to control their use. Pre- and postintervention hospital-onset CDI rates and antibiotic consumption were compared for a 20-month period from June 2010 to January 2012. Antibiotic usage was compared using defined daily dose, days of therapy, and number of courses prescribed. Comparisons used bivariate and regression techniques. Intervention facilities identified piperacillin/tazobactam, fluoroquinolones, or cefepime (odds ratio, 2.0-9.8 in CDI case patients compared with those without CDI) as intervention targets and selected several interventions (all included a component of audit and feedback). Varying degrees of success were observed in reducing antibiotic consumption over time. Total target antibiotic use significantly decreased (P < .05) when measured by days of therapy and number of courses but not by defined daily dose. Intravenous moxifloxacin and oral ciprofloxacin use showed significant reduction when measured by defined daily dose and days of therapy (P ≤ .01). Number of courses with all forms of these antibiotics was reduced (P < .005). Intervention hospitals reported fewer hospital-onset CDI cases (2.8 rate point difference) compared with nonintervention hospitals; however, we were unable to show statistically significant decreases in aggregate hospital-onset CDI either between intervention and nonintervention groups or within the intervention group over time. Although decreases in target antibiotic consumption did not translate into reductions of hospital-onset CDI in this study, many valuable lessons (including implementation strategies and antibiotic consumption measures) were learned. The findings can inform potential policy decisions regarding incorporating control of CDI and ASP as healthcare quality measures.


Long-term constant light induces constitutive elevated expression of mPER2 protein in the murine SCN: a molecular basis for Aschoff's rule?
Circadian rhythms in behavior, metabolism, and physiology are based upon transcriptional/translational feedback loops involving a core set of clock genes that interact to regulate their own expression. In mammals, the SCN is the site of a master biological clock regulating circadian locomotor rhythms. The products of the clock genes mPer1, mPer2, mCry1, and mCry2 form essential components of both negative and positive elements within the SCN oscillator. The primary aims of this study were to examine clock gene abundance under longterm LL in an attempt to provide molecular correlates of the lengthened tau and daily phase delays described by Aschoff's rule. Wheel-running behavior was recorded from mice maintained in either DD or LL for 50 days. The abundance of the clock genes mPer1, mPer2, mCry1, and mCry2 and their protein products was then examined (every approximately 4 h) within the SCN using in situ hybridization and immunocytochemistry. Under LL conditions, mPer1, mPer2, mCry1, and mCry2 messages remained rhythmic, although the waveform of mCry2 was altered compared to DD. In LL, mPER1, mCRY1, and mCRY2 protein levels were also rhythmic and comparable to the patterns observed in DD. However, mPER2 is elevated and constitutively expressed under LL. Thus, rhythmic expression of these clock genes is not dependent on the rhythmic production of mPER2, and the acute up-regulation of mPer1 and mPer2 described for short (nonparametric) light pulses is not sustained under LL conditions. These findings suggest that mPER2 is important for the generation of phase delays in the molecular clockwork, providing a possible molecular explanation for Aschoff's rule: LL lengthens the circadian period by inhibiting the degeneration of mPER2, and constitutively elevated levels of mPER2 enhance the phase-delaying limb of the molecular oscillator.


Trends in mortality after hospital admission for liver cirrhosis in an English population from 1968 to 1999.
Population based mortality rates from liver cirrhosis, and alcohol consumption, have increased sharply in Britain in the past 35 years. Little is known about the long term trends over time in mortality rates after hospital admission for liver cirrhosis. To analyse time trends in mortality in the year after admission for liver cirrhosis from 1968 to 1999. A total of 8192 people who were admitted to hospital in a defined population of Southern England. Analysis of hospital discharge statistics linked to death certificate data. The main outcome measures were case fatality rates (CFRs) and standardised mortality ratios (SMRs). At 30 days after admission, CFR was 15.9% and the SMR was 93 (86 in men and 102 in women, compared with 1 in the general population). At one year, the overall CFR was 33.6% and SMR was 16.3. There was no improvement from 1968 to 1999 in mortality rates. SMRs were highest for alcoholic cirrhosis of the liver (27.4 at one year) but lower for biliary cirrhosis (11.4) and chronic hepatitis (10.0). Mortality from most of the main causes of death, including accidents and suicides, was increased. The high mortality rates after hospital admission, and the fact that they have not fallen in the past 30 years, show that liver cirrhosis remains a disease with a very poor prognosis. Increased mortality from accidents, suicides, and mental disorders, particularly among those with alcoholic cirrhoses, indicates that prognosis is influenced by behavioural as well as by physical pathology.


G-quadruplexes significantly stimulate Pif1 helicase-catalyzed duplex DNA unwinding.
The evolutionarily conserved G-quadruplexes (G4s) are faithfully inherited and serve a variety of cellular functions such as telomere maintenance, gene regulation, DNA replication initiation, and epigenetic regulation. Different from the Watson-Crick base-pairing found in duplex DNA, G4s are formed via Hoogsteen base pairing and are very stable and compact DNA structures. Failure of untangling them in the cell impedes DNA-based transactions and leads to genome instability. Cells have evolved highly specific helicases to resolve G4 structures. We used a recombinant nuclear form of Saccharomyces cerevisiae Pif1 to characterize Pif1-mediated DNA unwinding with a substrate mimicking an ongoing lagging strand synthesis stalled by G4s, which resembles a replication origin and a G4-structured flap in Okazaki fragment maturation. We find that the presence of G4 may greatly stimulate the Pif1 helicase to unwind duplex DNA. Further studies reveal that this stimulation results from G4-enhanced Pif1 dimerization, which is required for duplex DNA unwinding. This finding provides new insights into the properties and functions of G4s. We discuss the observed activation phenomenon in relation to the possible regulatory role of G4s in the rapid rescue of the stalled lagging strand synthesis by helping the replicator recognize and activate the replication origin as well as by quickly removing the G4-structured flap during Okazaki fragment maturation.


Relation of C-reactive protein to body fat distribution and features of the metabolic syndrome in Europeans and South Asians.
To investigate the association between circulating C-reactive protein (CRP) concentrations and indices of body fat distribution and the insulin resistance syndrome in South Asians and Europeans. : Cross-sectional study. A total of 113 healthy South Asian and European men and women in West London (age 40-55 y, body mass index (BMI) 17-34 kg/m(2)). Fatness and fat distribution parameters (by anthropometry, dual-energy X-ray absorptiometry and abdominal CT scan); oral glucose tolerance test with insulin response; modified fat tolerance test; and CRP concentration by sensitive ELISA. Median CRP level in South Asian women was nearly double that in European women (1.35 vs 0.70 mg/1, P=0.05). Measures of obesity and CRP concentration were significantly associated in both ethnic groups. The correlation to CRP was especially strong among South Asians (P<0.01) for measures of central obesity (waist girth and visceral fat area), whereas BMI and percentage fat were more significantly associated with CRP in Europeans (P<0.05). In South Asians the associations of CRP with visceral fat area and waist girth persisted after adjustment for either BMI or percent fat (all, P<0.05). In age-, sex- and smoking-adjusted regression analyses CRP concentrations were significantly associated with fasting and 2 h insulin and lipid levels in both ethnic groups (P<0.05). When further statistical adjustment was made for visceral fat area these associations were abolished (P>0.15). We suggest that adiposity and in particular visceral adipose tissue is a key promoter of low-grade chronic inflammation. This observation may in part account for the association of CRP with markers of the metabolic syndrome. Future studies should confirm whether CRP concentrations are elevated in South Asians and whether losing weight by exercise or diet, or reduction in visceral fat mass, is associated with reduction in plasma CRP concentrations.


Oral lactoferrin for the treatment of sepsis and necrotizing enterocolitis in neonates.
Neonatal sepsis and necrotizing enterocolitis (NEC) cause significant neonatal mortality and morbidity in spite of appropriate antibiotic therapy. Enhancing host defence and modulating inflammation by using lactoferrin as an adjunct to antibiotics in the treatment of sepsis and/or NEC may improve clinical outcomes. The primary objective is to assess safety and efficacy of oral lactoferrin as an adjunct to antibiotics in the treatment of neonates with suspected or confirmed sepsis and/or NEC. Relevant trials in any language were searched in June 2008 in the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE (1966 - June 2008), PREMEDLINE, EMBASE (1980 - June 2008), CINAHL (1982 - June 2008), web sites: www.clinicaltrials.gov and www.controlled-trials.com, abstracts from the annual meeting of Pediatric Academic Societies (1990- June 2008), by contacting authors who have published in this field, from the reference lists of identified clinical trials and in the reviewer's personal files. Randomized or quasi-randomized controlled trials evaluating oral lactoferrin (at any dose or duration) used as an adjunct to antibiotic therapy compared with antibiotic therapy alone (with or without placebo) or other adjuncts to antibiotic therapy to treat neonates at any gestational age up to 44 weeks postmenstrual age with confirmed or suspected sepsis or necrotizing enterocolitis (Bell's Stage II or III). We used the standardized methods of the Cochrane Neonatal Review Group (CNRG) for conducting a systematic review and for assessing the methodological quality of the studies (http://neonatal.cochrane.org/en/index.html). The titles and the abstracts of studies identified by the search strategy were independently assessed by the two review authors and full text version was obtained for assessment if necessary. Forms were designed for trial inclusion/exclusion and data extraction. Our search strategy did not identify any eligible trials or potentially eligible ongoing neonatal trials. One trial was excluded and three ongoing or soon to be started adult trials using lactoferrin for the treatment of infections were identified. Currently there is no evidence to recommend or refute the use of lactoferrin for the treatment of neonatal sepsis or necrotizing enterocolitis as an adjunct to antibiotic therapy. The safety and efficacy of different preparations and doses of lactoferrin needs to be established in neonates. Well designed adequately powered randomized multicenter trials are needed to address the efficacy and safety of lactoferrin in the treatment of neonatal sepsis and necrotizing enterocolitis. These trials should evaluate long-term neurodevelopmental and pulmonary outcomes in addition to short-term outcomes (e.g. mortality).


Short-Term Stable Isotope Probing of Proteins Reveals Taxa Incorporating Inorganic Carbon in a Hot Spring Microbial Mat.
The upper green layer of the chlorophototrophic microbial mats associated with the alkaline siliceous hot springs of Yellowstone National Park consists of oxygenic cyanobacteria (Synechococcus spp.), anoxygenic Roseiflexus spp., and several other anoxygenic chlorophototrophs. Synechococcus spp. are believed to be the main fixers of inorganic carbon (Ci), but some evidence suggests that Roseiflexus spp. also contribute to inorganic carbon fixation during low-light, anoxic morning periods. Contributions of other phototrophic taxa have not been investigated. In order to follow the pathway of Ci incorporation into different taxa, mat samples were incubated with [13C]bicarbonate for 3 h during the early-morning, low-light anoxic period. Extracted proteins were treated with trypsin and analyzed by mass spectrometry, leading to peptide identifications and peptide isotopic profile signatures containing evidence of 13C label incorporation. A total of 25,483 peptides, corresponding to 7,221 proteins, were identified from spectral features and associated with mat taxa by comparison to metagenomic assembly sequences. A total of 1,417 peptides, derived from 720 proteins, were detectably labeled with 13C. Most 13C-labeled peptides were derived from proteins of Synechococcus spp. and Roseiflexus spp. Chaperones and proteins of carbohydrate metabolism were most abundantly labeled. Proteins involved in photosynthesis, Ci fixation, and N2 fixation were also labeled in Synechococcus spp. Importantly, most proteins of the 3-hydroxypropionate bi-cycle for Ci fixation in Roseiflexus spp. were labeled, establishing that members of this taxocene contribute to Ci fixation. Other taxa showed much lower [13C]bicarbonate incorporation.IMPORTANCE Yellowstone hot spring mats have been studied as natural models for understanding microbial community ecology and as modern analogs of stromatolites, the earliest community fossils on Earth. Stable-isotope probing of proteins (Pro-SIP) permitted short-term interrogation of the taxa that are involved in the important process of light-driven Ci fixation in this highly active community and will be useful in linking other metabolic processes to mat taxa. Here, evidence is presented that Roseiflexus spp., which use the 3-hydroxypropionate bi-cycle, are active in Ci fixation. Because this pathway imparts a lower degree of selection of isotopically heavy Ci than does the Calvin-Benson-Bassham cycle, the results suggest a mechanism to explain why the natural abundance of 13C in mat biomass is greater than expected if only the latter pathway were involved. Understanding how mat community members influence the 13C/12C ratios of mat biomass will help geochemists interpret the 13C/12C ratios of organic carbon in the fossil record.


A Comparative Study of Variables Influencing Ischemic Injury in the Longa and Koizumi Methods of Intraluminal Filament Middle Cerebral Artery Occlusion in Mice.
The intraluminal filament model of middle cerebral artery occlusion (MCAO) in mice and rats has been plagued by inconsistency, owing in part to the multitude of variables requiring control. In this study we investigated the impact of several major variables on survival rate, lesion volume, neurological scores, cerebral blood flow (CBF) and body weight including filament width, time after reperfusion, occlusion time and the choice of surgical method. Using the Koizumi method, we found ischemic injury can be detected as early as 30 min after reperfusion, to a degree that is not statistically different from 24 h post-perfusion, using 2,3,5-Triphenyltetrazolium chloride (TTC) staining. We also found a distinct increase in total lesion volume with increasing occlusion time, with 30-45 min a critical time for the development of large, reproducible lesions. Furthermore, although we found no significant difference in total lesion volume generated by the Koizumi and Longa methods of MCAO, nor were survival rates appreciably different between the two at 4 h after reperfusion, the Longa method produces significantly greater reperfusion. Finally, we found no statistical evidence to support the exclusion of data from animals experiencing a CBF reduction of <70% in the MCA territory following MCAO, using laser-Doppler flowmetry. Instead we suggest the main usefulness of laser-Doppler flowmetry is for guiding filament placement and the identification of subarachnoid haemorrhages and premature reperfusion. In summary, this study provides detailed evaluation of the Koizumi method of intraluminal filament MCAO in mice and a direct comparison to the Longa method.


Repetitive Transcranial Magnetic Stimulation (rTMS) Treatment of Depression and Anxiety in a Patient with Anorexia Nervosa.
Anorexia nervosa (AN) is characterized by restricted eating, emaciation, and distorted body image and tends to be a chronic and deadly disorder with a high risk of developing a relapsing course described as a severe and enduring anorexia. This case study reports a patient with AN with comorbid depression and anxiety who was treated by repetitive transcranial magnetic stimulation (rTMS). Our patient's first hospitalization in our ED clinic was at the age of 25 in 2012. Her anorexia symptoms have been developing over 1.5 years. The body mass index (BMI) at admission was 12.21 kg/m². She was stimulated by use of a MAGSTIM Super Rapid 2 device, every Monday through Friday (5 days a week) with the frequency 10 Hz, 15 trains/day, 100 pulses/train, intertrain interval 107 s for 10 days. The specific spot of stimulation was over the left DLPFC. The therapy was evaluated, both by the team and by the patient, as ineffective. Shortly after the therapy was finished, the patient was discharged with final weight of 46 kg and BMI 13.15 kg/m². We showed, that despite our positive clinical experiences with rTMS therapy in depression and anxiety, the treatment of AN and comorbid depressive disorder with anxious distress, our patient's anorexic, anxious, and depressive symptoms remained unaffected. In this case, only invasive medical intervention helped the patient to reach normal weight, but without any significant changes in her psychology. This case study shows the need for further investigation of the influence that body weight might have and whether the number of sessions has an effect on rTMS efficacy.


Priming winter wheat seeds with the bacterial quorum sensing signal N-hexanoyl-L-homoserine lactone (C6-HSL) shows potential to improve plant growth and seed yield.
Several model plants are known to respond to bacterial quorum sensing molecules with altered root growth and gene expression patterns and induced resistance to plant pathogens. These compounds may represent novel elicitors that could be applied as seed primers to enhance cereal crop resistance to pathogens and abiotic stress and to improve yields. We investigated whether the acyl-homoserine lactone N-hexanoyl-L-homoserine lactone (C6-HSL) impacted winter wheat (Triticum aestivum L.) seed germination, plant development and productivity, using two Ukrainian varieties, Volodarka and Yatran 60, in both in vitro experiments and field trials. In vitro germination experiments indicated that C6-HSL seed priming had a small but significant positive impact on germination levels (1.2x increase, p < 0.0001), coleoptile and radicle development (1.4x increase, p < 0.0001). Field trials over two growing seasons (2015-16 and 2016-17) also demonstrated significant improvements in biomass at the tillering stage (1.4x increase, p < 0.0001), and crop structure and productivity at maturity including grain yield (1.4-1.5x increase, p < 0.0007) and quality (1.3x increase in good grain, p < 0.0001). In some cases variety effects were observed (p ≤ 0.05) suggesting that the effect of C6-HSL seed priming might depend on plant genetics, and some benefits of priming were also evident in F1 plants grown from seeds collected the previous season (p ≤ 0.05). These field-scale findings suggest that bacterial acyl-homoserine lactones such as C6-HSL could be used to improve cereal crop growth and yield and reduce reliance on fungicides and fertilisers to combat pathogens and stress.


Psychosocial interventions for bipolar disorder: a review of literature and introduction of the systematic treatment enhancement program.
What is the evidence that psychosocial treatment adds to the efficacy of pharmacotherapy in forestalling episodes of bipolar disorder (BPD)? This article give s the rationale for including psychosocial intervention in the outpatient maintenance of BPD. Attention is placed on the three psychosocial modalities that have achieved empirical support in randomized trials: family psychoeducational treatment, cognitive-behavioral therapy, and interpersonal and social rhythm therapy. These three treatments are being contrasted with a psychosocial control condition in the context of the ongoing, multi-center Systematic Treatment Enhancement Program for Bipolar Disorder (STEP - BD). The objectives, design, and potential contributions of the STEP-BD study are explained. Future directions for the evaluation and dissemination of manual-based psychosocial interventions are discussed.


Real-time PCR assays of single-nucleotide polymorphisms defining the major Brucella clades.
Members of the genus Brucella are known worldwide as pathogens of wildlife and livestock and are the most common organisms of zoonotic infection in humans. In general, brucellae exhibit a range of host specificity in animals that has led to the identification of at least seven Brucella species. The genomes of the various Brucella species are highly conserved, which makes the differentiation of species highly challenging. However, we found single-nucleotide polymorphisms (SNPs) in housekeeping and other genes that differentiated the seven main Brucella species or clades and thus enabled us to develop real-time PCR assays based around these SNPs. Screening of a diverse panel of 338 diverse isolates with these assays correctly identified each isolate with its previously determined Brucella clade. Six of the seven clade-specific assays detected DNA concentrations of less than 10 fg, indicating a high level of sensitivity. This SNP-based approach places samples into a phylogenetic framework, allowing reliable comparisons to be made among the lineages of clonal bacteria and providing a solid basis for genotyping. These PCR assays provide a rapid and highly sensitive method of differentiating the major Brucella groups that will be valuable for clinical and forensic applications.


[Optimization of the dosage schedule for sustaining intrinsic biological rhythms].
One of the most indispensable biological functions for all living organisms is the circadian clock, which acts like a multifunctional timer to regulate the homeostatic system including sleep and wakefulness, hormonal secretions, and various other body functions in a 24-hour cycle. Recent molecular dissections of the circadian biological clock system have revealed that oscillation in the transcription of specific clock genes plays a central role in the generation of circadian rhythms. Several drugs can affect the expression of clock genes, resulting in alteration of the 24-hour rhythms in physiology and behavior. Here, we report the disruptive effect of interferon (IFN) on the core circadian oscillation mechanism. Treatment of cultured hepatic cells with IFN-alpha caused a significant reduction in Clock and Bmal1 mRNA levels, which are positive regulators of circadian output rhythm, leading to a decrease in their protein levels. The continuous administration of IFN-alpha significantly decreased CLOCK and BMAL1 protein levels in the suprachiasmatic nucleus and liver of mice, thereby preventing oscillations in the expression of clock and clock-controlled output genes. These findings reveal a possible pharmacologic action of IFN-alpha on the core circadian oscillation mechanism and indicate that the disruptive effect of IFN-alpha on circadian output function is the underlying cause of its adverse effects on 24-hour rhythms in physiology and behavior. Furthermore, the alteration of clock function, a new concept of adverse effects, can be avoided by altering the dosage schedule of IFN-alpha to minimize the adverse drug effect on clock gene expression. One approach for increasing the efficacy of pharmacotherapy is administering drugs at the time of day when they are best tolerated. Attention should be paid to the alteration of clock gene expression, and it should be considered an adverse effect when it leads to altered circadian organization of the molecular clockwork which is a serious problem affecting basic function of living organisms.


Proof of concept, randomized, placebo-controlled study of the effect of simvastatin on the course of age-related macular degeneration.
HMG Co-A reductase inhibitors are ubiquitous in our community yet their potential role in age-related macular degeneration (AMD) remains to be determined. To evaluate the effect of simvastatin on AMD progression and the effect modification by polymorphism in apolipoprotein E (ApoE) and complement factor H (CFH) genes. A proof of concept double-masked randomized controlled study. 114 participants aged 53 to 91 years, with either bilateral intermediate AMD or unilateral non-advanced AMD (with advanced AMD in fellow eye), BCVA ≥ 20/60 in at least one eye, and a normal lipid profile. Simvastatin 40 mg/day or placebo, allocated 1:1. Progression of AMD either to advanced AMD or in severity of non-advanced AMD. Results. The cumulative AMD progression rates were 70% in the placebo and 54% in the simvastatin group. Intent to treat multivariable logistic regression analysis, adjusted for age, sex, smoking and baseline AMD severity, showed a significant 2-fold decrease in the risk of progression in the simvastatin group: OR 0.43 (0.18-0.99), p = 0.047. Post-hoc analysis stratified by baseline AMD severity showed no benefit from treatment in those who had advanced AMD in the fellow eye before enrolment: OR 0.97 (0.27-3.52), p = 0.96, after adjusting for age, sex and smoking. However, there was a significant reduction in the risk of progression in the bilateral intermediate AMD group compared to placebo [adjusted OR 0.23 (0.07-0.75), p = 0.015]. The most prominent effect was observed amongst those who had the CC (Y402H) at risk genotype of the CFH gene [OR 0.08 (0.02-0.45), p = 0.004]. No evidence of harm from simvastatin intervention was detected. Simvastatin may slow progression of non-advanced AMD, especially for those with the at risk CFH genotype CC (Y402H). Further exploration of the potential use of statins for AMD, with emphasis on genetic subgroups, is warranted. Australian New Zealand Clinical Trial Registry (ANZCTR) ACTRN1260500032065.