SCL-mediated regulation of the cell-cycle regulator p21 is critical for murine megakaryopoiesis.
Megakaryopoiesis is a complex process that involves major cellular and nuclear changes and relies on controlled coordination of cellular proliferation and differentiation. These mechanisms are orchestrated in part by transcriptional regulators. The key hematopoietic transcription factor stem cell leukemia (SCL)/TAL1 is required in early hematopoietic progenitors for specification of the megakaryocytic lineage. These early functions have, so far, prevented full investigation of its role in megakaryocyte development in loss-of-function studies. Here, we report that SCL critically controls terminal megakaryocyte maturation. In vivo deletion of Scl specifically in the megakaryocytic lineage affects all key attributes of megakaryocyte progenitors (MkPs), namely, proliferation, ploidization, cytoplasmic maturation, and platelet release. Genome-wide expression analysis reveals increased expression of the cell-cycle regulator p21 in Scl-deleted MkPs. Importantly, p21 knockdown-mediated rescue of Scl-mutant MkPs shows full restoration of cell-cycle progression and partial rescue of the nuclear and cytoplasmic maturation defects. Therefore, SCL-mediated transcriptional control of p21 is essential for terminal maturation of MkPs. Our study provides a mechanistic link between a major hematopoietic transcriptional regulator, cell-cycle progression, and megakaryocytic differentiation.


Retinal axon divergence in the optic chiasm: uncrossed axons diverge from crossed axons within a midline glial specialization.
A long-standing question is how fiber pathways in the mammalian CNS project to both sides of the brain. Static and real-time analyses of dye-labeled retinal axons (Godement et al., 1990, 1994) have demonstrated that at embryonic day 15-17 in the mouse, crossed and uncrossed axons from each eye diverge in a zone 100-200 microns proximal to the midline of the optic chiasm. In this study, we identify cellular specializations in this zone that might serve as cues for retinal axon divergence. Second, using growth cone morphology as an indicator of growth cone destination, we analyzed how crossed and uncrossed retinal growth cones related to these cellular components. Monoclonal antibody RC2, a marker for radial glia in embryonic mouse CNS, revealed a palisade of radial glia straddling the midline. At the midline, a thin raphe of cells that appear morphologically distinct from the radial glia express a free carbohydrate epitope, stage-specific embryonic antigen 1 (SSEA-1). Sections containing Dil-labeled axons and immunolabeled cells indicated that all axons enter the radial glial palisade. Uncrossed axons turn within the palisade, but never beyond the raphe of SSEA-1-positive cells. In addition, ultrastructural analysis indicated that all growth cones contact radial glia, with projections of the growth cone interdigitating with glial fibers. These results demonstrate that retinal axons diverge within a cellular specialization centered around the midline of the developing optic chiasm, consistent with the hypothesis that cues for divergence are located in this zone.


Preliminary clinic study on computer assisted mandibular reconstruction: the positive role of surgical navigation technique.
The objectives of the present study were to investigate the reliability and outcomes of computer-assisted techniques in mandibular reconstruction with a fibula flap and verify whether the surgical navigation system was feasible in mandible reconstructive surgery. Eight cases were enrolled in the computer assisted surgery (CAS) group and 14 cases in the traditional group. The shaping and fixation of the fibula grafts were guided by computer assisted techniques, which could be monitored with the BrainLAB surgical navigation system. The variation of mandible configuration was evaluated by CT measurement in the Mimics software, including the variation of length, width, height and gonial angle of the mandible. The 3D facial soft tissue alteration was also analyzed in 3D chromatogram by Geomagic software. All 22 fibula flaps survived. The mandibular configurations and facial contours had a better clinic result in the CAS group. The length, width, height and gonial angle of the reconstructive mandible were more similar to the original one. The Wilcoxon rank sum test analysis suggested significant differences in the measurements. The chromatographic analysis also visually showed superiority over the traditional group. The computer assisted surgical navigation method used in mandibular reconstruction is feasible and precise for clinical application. The contour of the reconstructed mandible and facial symmetry are improved with computer techniques.


Nurses' behavioural intentions towards self-poisoning patients: a theory of reasoned action, comparison of attitudes and subjective norms as predictive variables.
The incidence of self-poisoning is on the increase. Most patients who self-poison are dealt with initially in the general hospital. Therefore, the type and quality of care self-poisoning patients receive will depend, in part, on how they are viewed by nursing staff within the general hospital setting. A knowledge and understanding of the attitudes held by nurses towards self-poisoning patients is therefore important to those involved in the planning and delivery of care towards this client group. Previous studies have examined health care professionals' attitudes towards people who self-poison. Usually, however, these have not focused specifically on nurses' attitudes, and they have ignored the relationship between the attitudes expressed by staff and their intentions to engage in subsequent caring behaviour of one sort or another. It is hence unclear how the findings of such studies are relevant or applicable to nursing policy and practice. The present study aims to address these limitations using a methodology informed by the theory of reasoned action. The study aims to separate out the distinctive roles played by nurses' own attitudes, and the social pressures represented by other people's attitudes, in determining the types of caring behaviour in which nurses intend to engage when dealing with self-poisoning patients. The study adopts a questionnaire-based approach incorporating two specially designed vignettes. The results show that nurses' own attitudes, and what they believe about the attitudes of others, predict their behavioural intentions towards self-poisoning patients. The study also shows that nurses with a more positive orientation towards self-poisoning patients differ in behavioural and normative beliefs from nurses who have a less positive orientation. The implications for future attempts to explore the relationship between nurses' attitudes and subsequent caring behaviour are considered, along with implications for nursing policy and practice.


Activation of human monocytic cells by lysophosphatidic acid and sphingosine-1-phosphate.
Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are serum-borne lipid mediators with potential proinflammatory and atherogenic properties. We studied the effects of LPA and S1P on [Ca(2+)](i), a second messenger of cellular activation, in human monocytic Mono Mac 6 (MM6) cells. LPA and S1P induced [Ca(2+)](i) transients with EC(50) values of 47 and 340 nM, respectively. Ca(2+) signals evoked by LPA and S1P originated mainly from the stimulation of Ca(2+) entry, were blocked by the phospholipase C inhibitor U73122, and were inhibited by pertussis toxin. The LPA(1) and LPA(3) receptor antagonist dioctylglycerol pyrophosphate inhibited the LPA-induced Ca(2+) signal. Notably, serum and minimally modified LDL (mm-LDL) evoked [Ca(2+)](i) increases that were mediated entirely through activation of LPA receptors. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis showed the presence of the LPA and S1P receptor subtypes LPA(1), LPA(2,) S1P(1), S1P(2), S1P(4) in MM6 cells, human monocytes and macrophages. Together these results indicate that LPA, mm-LDL and serum induce via activation of the LPA(1) receptor a G(i)/phospholipase C/Ca(2+) signalling pathway in monocytes. Our study is the first report showing the receptor-mediated activation of human monocytic cells by low nanomolar concentrations of LPA and S1P, and suggests a role of these lipid mediators in inflammation and atherogenesis.


Reflectivity of a disordered monolayer estimated by graded refractive index and scattering models.
Reflectivity of a random monolayer, consisting of transparent spherical particles, is estimated using a graded refractive index model, an effective medium approach, and two scattering models. Two cases, a self-standing film and one with a substrate, are considered. Neither the surrounding medium nor the substrate are absorbing materials. Results at normal incidence, with different particle sizes, covering ratios and refractive indexes, are compared. The purpose of this work is to find under which circumstances, for reflectivity at normal incidence, a particle monolayer behaves as a graded refractive index film.


Absence of vertical transmission of infectious salmon anemia virus (ISAV) from individually infected Atlantic salmon Salmo salar.
Atlantic salmon Salmo salar L. eggs were collected from grilse that were individually identified as ISAV-positive based on the detection of pathogen in ovarian fluid by RT-PCR. The eggs were fertilised, disinfected and reared under quarantine conditions. To address the possibility of vertical transmission, fertilised eggs, alevins and parr were screened for the virus by SHK-1 cell culture and RT-PCR. In addition, ISAV-negative parr were injected with homogenates of potentially infected eyed eggs. ISAV was not detected in eyed eggs, alevins or parr. No mortalities occurred among fish injected with the egg homogenates. These observations suggest the absence of a vertical transmission route for ISAV infection.


The effects of opioids on HIV reactivation in latently-infected T-lymphoblasts.
Opioids may have effects on susceptibility to HIV-infection, viral replication and disease progression. Injecting drug users (IDU), as well as anyone receiving opioids for anesthesia and analgesia may suffer the clinical consequences of such interactions. There is conflicting data between in vitro experiments showing an enhancing effect of opioids on HIV replication and clinical data, mostly showing no such effect. For clarification we studied the effects of the opioids heroin and morphine on HIV replication in cultured CD4-positive T cells at several concentrations and we related the observed effects with the relevant reached plasma concentrations found in IDUs. Latently-infected ACH-2 T lymphoblasts were incubated with different concentrations of morphine and heroine. Reactivation of HIV was assessed by intracellular staining of viral Gag p24 protein and subsequent flow cytometric quantification of p24-positive cells. The influence of the opioid antagonist naloxone and the antioxidants N-acetyl-cysteine (NAC) and glutathione (GSH) on HIV reactivation was determined. Cell viability was investigated by 7-AAD staining and flow cytometric quantification. Morphine and heroine triggered reactivation of HIV replication in ACH-2 cells in a dose-dependent manner at concentrations above 1 mM (EC50 morphine 2.82 mM; EC50 morphine 1.96 mM). Naloxone did not interfere with heroine-mediated HIV reactivation, even at high concentrations (1 mM). Opioids also triggered necrotic cell death at similar concentrations at which HIV reactivation was observed. Both opioid-mediated reactivation of HIV and opioid-triggered cell death could be inhibited by the antioxidants GSH and NAC. Opioids reactivate HIV in vitro but at concentrations that are far above the plasma levels of analgesic regimes or drug concentrations found in IDUs. HIV reactivation was mediated by effects unrelated to opioid-receptor activation and was tightly linked to the cytotoxic activity of the substances at millimolar concentrations, suggesting that opioid-mediated reactivation of HIV was due to accompanying effects of cellular necrosis such as activation of reactive oxygen species and NF-κB.


Improvement in Saccharification Yield of Mixed Rumen Enzymes by Identification of Recalcitrant Cell Wall Constituents Using Enzyme Fingerprinting.
Identification of recalcitrant factors that limit digestion of forages and the development of enzymatic approaches that improve hydrolysis could play a key role in improving the efficiency of meat and milk production in ruminants. Enzyme fingerprinting of barley silage fed to heifers and total tract indigestible fibre residue (TIFR) collected from feces was used to identify cell wall components resistant to total tract digestion. Enzyme fingerprinting results identified acetyl xylan esterases as key to the enhanced ruminal digestion. FTIR analysis also suggested cross-link cell wall polymers as principal components of indigested fiber residues in feces. Based on structural information from enzymatic fingerprinting and FTIR, enzyme pretreatment to enhance glucose yield from barley straw and alfalfa hay upon exposure to mixed rumen-enzymes was developed. Prehydrolysis effects of recombinant fungal fibrolytic hydrolases were analyzed using microassay in combination with statistical experimental design. Recombinant hemicellulases and auxiliary enzymes initiated degradation of plant structural polysaccharides upon application and improved the in vitro saccharification of alfalfa and barley straw by mixed rumen enzymes. The validation results showed that microassay in combination with statistical experimental design can be successfully used to predict effective enzyme pretreatments that can enhance plant cell wall digestion by mixed rumen enzymes.


Unexpected Nongenetic Individual Heterogeneity and Trait Covariance in Daphnia and Its Consequences for Ecological and Evolutionary Dynamics.
Individual differences in genetics, age, or environment can cause tremendous differences in individual life-history traits. This individual heterogeneity generates demographic heterogeneity at the population level, which is predicted to have a strong impact on both ecological and evolutionary dynamics. However, we know surprisingly little about the sources of individual heterogeneity for particular taxa or how different sources scale up to impact ecological and evolutionary dynamics. Here we experimentally study the individual heterogeneity that emerges from both genetic and nongenetic sources in a species of freshwater zooplankton across a large gradient of food quality. Despite the tight control of environment, we still find that the variation from nongenetic sources is greater than that from genetic sources over a wide range of food quality and that this variation has strong positive covariance between growth and reproduction. We evaluate the general consequences of genetic and nongenetic covariance for ecological and evolutionary dynamics theoretically and find that increasing nongenetic variation slows evolution independent of the correlation in heritable life-history traits but that the impact on ecological dynamics depends on both nongenetic and genetic covariance. Our results demonstrate that variation in the relative magnitude of nongenetic versus genetic sources of variation impacts the predicted ecological and evolutionary dynamics.


The Impact of Clinical Trials Conducted by Research Networks in Pediatric Critical Care.
Research networks in adult and neonatal critical care have demonstrated collaborative and successful execution of clinical trials. Such networks appear to have been relatively recently established in the field of pediatric critical care. The objective of this study was to evaluate the productivity and impact of randomized controlled trials conducted by pediatric critical care research networks, compared with nonnetwork trials. We searched multiple online databases including MEDLINE, reference lists of randomized controlled trials, and relevant systematic reviews. Independent pairs of reviewers identified published randomized controlled trials administering any intervention to children in a PICU and abstracted data. A research network was defined as a formal consortium or collaborative research group established for the purpose of conducting clinical research. Data were independently abstracted in duplicate. There were 288 pediatric critical care randomized controlled trials published in English between 1986 and July 2015, of which 15 randomized controlled trials (5.2%) were conducted by a total of five research networks. Network randomized controlled trials were more often multicentered, multinational, and larger in size (p < 0.001), compared with nonnetwork randomized controlled trials. Accordingly, their trials took longer to complete (median, 36 vs 21 mo; p < 0.001). Early stopping occurred in 46.7% of network randomized controlled trials (46.7%) and 27% of nonnetwork randomized controlled trials (p = 0.14), most commonly for futility. None of the network, but 45% of the nonnetwork trials found a significant difference in their primary outcome (p < 0.001). Network trials were more frequently cited (median, 6 vs 2 citations per year) and published in higher impact journals (median impact factor, 21.8 vs 3; p < 0.001). Research networks have conducted a minority of randomized controlled trials in pediatric critical care. They infrequently demonstrate significant differences in their primary outcomes. Despite this, network trials are cited more frequently and appear to have greater impact. There are important lessons to learn from both individual researchers as well as research networks that may guide the successful conduct of collaborative, high-quality randomized controlled trials in critically ill children.


Impact of chronic kidney disease on use of evidence-based therapy in stable coronary artery disease: a prospective analysis of 22,272 patients.
To assess the frequency of chronic kidney disease (CKD), define the associated demographics, and evaluate its association with use of evidence-based drug therapy in a contemporary global study of patients with stable coronary artery disease. 22,272 patients from the ProspeCtive observational LongitudinAl RegIstry oF patients with stable coronary arterY disease (CLARIFY) were included. Baseline estimated glomerular filtration rate (eGFR) was calculated (CKD-Epidemiology Collaboration formula) and patients categorised according to CKD stage: >89, 60-89, 45-59 and <45 mL/min/1.73 m2. Mean (SD) age was 63.9±10.4 years, 77.3% were male, 61.8% had a history of myocardial infarction, 71.9% hypertension, 30.4% diabetes and 75.4% dyslipidaemia. Chronic kidney disease (eGFR<60 mL/min/1.73 m2) was seen in 22.1% of the cohort (6.9% with eGFR<45 mL/min/1.73 m2); lower eGFR was associated with increasing age, female sex, cardiovascular risk factors, overt vascular disease, other comorbidities and higher systolic but lower diastolic blood pressure. High use of secondary prevention was seen across all CKD stages (overall 93.4% lipid-lowering drugs, 95.3% antiplatelets, 75.9% beta-blockers). The proportion of patients taking statins was lower in patients with CKD. Antiplatelet use was significantly lower in patients with CKD whereas oral anticoagulant use was higher. Angiotensin-converting enzyme inhibitor use was lower (52.0% overall) and inversely related to declining eGFR, whereas angiotensin-receptor blockers were more frequently prescribed in patients with reduced eGFR. Chronic kidney disease is common in patients with stable coronary artery disease and is associated with comorbidities. Whilst use of individual evidence-based medications for secondary prevention was high across all CKD categories, there remains an opportunity to improve the proportion who take all three classes of preventive therapies. Angiotensin-converting enzyme inhibitors were used less frequently in lower eGRF categories. Surprisingly the reverse was seen for angiotensin-receptor blockers. Further evaluation is required to fully understand these associations. The CLARIFY (ProspeCtive observational LongitudinAl RegIstry oF patients with stable coronary arterY disease) Registry is registered in the ISRCTN registry of clinical trials with the number ISRCTN43070564. http://www.controlled-trials.com/ISRCTN43070564.


The status of the species Bacillus aerophilus and Bacillus stratosphericus. Request for an Opinion.
During a study assessing the diversity of the Bacillus pumilus group it became apparent that the type strains of both Bacillus aerophilus and Bacillus stratosphericus were not available from any established culture collection, nor from the authors who originally described them. Therefore, type strains of these species cannot be included in any further scientific studies. It is therefore proposed that the Judicial Commission of the International Committee of Systematics of Prokaryotes place the names Bacillus aerophilus and Bacillus stratosphericus on the list of rejected names, if suitable replacements for the type strains are not found or if neotype strains are not proposed within two years following the publication of this Request for an Opinion.


Does diabetes disease management save money and improve outcomes? A report of simultaneous short-term savings and quality improvement associated with a health maintenance organization-sponsored disease management program among patients fulfilling health employer data and information set criteria.
Little is known about the impact of disease management programs on medical costs for patients with diabetes. This study compared health care costs for patients who fulfilled health employer data and information set (HEDIS) criteria for diabetes and were in a health maintenance organization (HMO)-sponsored disease management program with costs for those not in disease management. We retrospectively examined paid health care claims and other measures of health care use over 2 years among 6,799 continuously enrolled Geisinger Health Plan patients who fulfilled HEDIS criteria for diabetes. Two groups were compared: those who were enrolled in an opt-in disease management program and those who were not enrolled. We also compared HEDIS data on HbA(1c) testing, percent not in control, lipid testing, diabetic eye screening, and kidney disease screening. All HEDIS measures were based on a hybrid method of claims and chart audits, except for percent not in control, which was based on chart audits only. Of 6,799 patients fulfilling HEDIS criteria for the diagnosis of diabetes, 3,118 (45.9%) patients were enrolled in a disease management program (program), and 3,681 (54.1%) were not enrolled (nonprogram). Both groups had similar male-to-female ratios, and the program patients were 1.4 years younger than the nonprogram patients. Per member per month paid claims averaged 394.62 dollars for program patients compared with 502.48 dollars for nonprogram patients (P < 0.05). This difference was accompanied by lower inpatient health care use in program patients (mean of 0.12 admissions per patient per year and 0.56 inpatient days per patient per year) than in nonprogram patients (0.16 and 0.98, P < 0.05 for both measures). Program patients experienced fewer emergency room visits (0.49 per member per year) than nonprogram patients (0.56) but had a higher number of primary care visits (8.36 vs. 7.78, P < 0.05 for both measures). Except for emergency room visits, these differences remained statistically significant after controlling for age, sex, HMO enrollment duration, presence of a pharmacy benefit, and insurance type. Program patients also achieved higher HEDIS scores for HbA(1c) testing as well as for lipid, eye, and kidney screenings (96.6, 91.1, 79.1, and 68.5% among program patients versus 83.8, 77.6, 64.9, and 39.3% among nonprogram patients, P < 0.05 for all measures). Among 1,074 patients with HbA(1c) levels measured in a HEDIS chart audit, 35 of 526 (6.7%) program patients had a level >9.5%, as compared with 79 of 548 (14.4%) nonprogram patients. In this HMO, an opt-in disease management program appeared to be associated with a significant reduction in health care costs and other measures of health care use. There was also a simultaneous improvement in HEDIS measures of quality care. These data suggest that disease management may result in savings for sponsored managed care organizations and that improvements in HEDIS measures are not necessarily associated with increased medical costs.


Art and the brain: a view from dementia.
Art making encompasses a range of perceptual and cognitive functions involving widely distributed brain systems. The dementias impact on these systems in different ways, raising the possibility that each dementia has a unique artistic signature. Here we use a review of the visual art of 14 artists with dementia (five Alzheimer's disease, seven fronto-temporal dementia and two dementia with Lewy bodies) to further our understanding of the neurobiological constituents of art production and higher artistic function. Artists with Alzheimer's disease had prominent changes in spatial aspects of their art and attributes of colour and contrast. These qualities were preserved in the art of fronto-temporal dementia, which was characterised by perseverative themes and a shift towards realistic representation. The art of dementia with Lewy Bodies was characterised by simple, bizarre content. The limitations of using visual aspects of individual artworks to infer the impact of dementia on art production are discussed with the need for a wider perspective encompassing changes in cognition, emotion, creativity and artistic personality. A novel classificatory scheme is presented to help characterise neural mechanisms of higher artistic functions in future studies.


Cannabinoid Hyperemesis Syndrome Survey and Genomic Investigation.
Background: Cannabinoid hyperemesis syndrome (CHS) is a diagnosis of exclusion with intractable nausea, cyclic vomiting, abdominal pain, and hot bathing behavior associated with ongoing tetrahydrocannabinol (THC) exposure. Increasing cannabis use may elevate CHS prevalence, exacerbating a public health issue with attendant costs and morbidity. Objective, Design, and Data Source: This study, the largest contemporaneous database, investigated genetic mutations underlying CHS. Patients with CHS diagnosis and ongoing symptoms were compared with current cannabis users lacking symptoms. Target Population: A screening questionnaire was posted online. Of 585 respondents, 205 qualified as the CHS pool and 54 as controls; a reduced pool of 28 patients and 12 controls ultimately completed genomic testing. Results: Patients and controls were high-frequency users of cannabis flower or concentrates (93%), using multiple grams/day of THC-predominant material. Among patients, 15.6% carried diagnoses of cannabis dependency or addiction, and 56.6% experienced withdrawal symptoms. About 87.7% of patients improved after cannabis cessation, most suffering recurrence rapidly after resumption. Findings in patients included mutations in genes COMT {odds ratio, 12 (95% confidence limit [CL], 1.3-88.1) p=0.012}, transient receptor potential vanilloid receptor 1 (TRPV1) (odds ratio, 5.8 [95% CL, 1.2-28.4] p=0.015), CYP2C9 (odds ratio, 7.8 [95% CL, 1.1-70.1] p=0.043), gene coding dopamine-2 receptor (DRD2) (odds ratio, 6.2 [95% CL, 1.1-34.7] p=0.031), and ATP-binding cassette transporter gene (ABCA1) (odds ratio, 8.4 [95% CL, 1.5-48.1] p=0.012). Limitations: Some participants were reluctant to undergo genetic testing; only 28 of 99 CHS patients who agreed to testing ultimately returned a kit. Conclusion: This is the largest patient cohort of CHS examined to date, and first to note associated mutations in genes affecting neurotransmitters, the endocannabinoid system, and the cytochrome P450 complex associated with cannabinoid metabolism. Although the sample size was smaller than desired, these preliminary findings may contribute to the growing body of knowledge, stimulate additional investigation, help elucidate the pathophysiology of CHS, and, ultimately, direct future treatment.


Orbital decomposition for ill-behaved event sequences: transients and superordinate structures.
Time series analysis is often challenged by the presence of transient functions. We examined some types of transients found in time series of events that lend themselves to symbolic dynamics analysis through the method of orbital decomposition, which is based on the principle that chaotic series arise from coupled oscillators. Synthetic data sets were constructed to study the impact of intrusive events, intrusive series, merged functions, non-coupled oscillators, and driving oscillations on the patterns of final statistics obtained from orbital decomposition analysis. Two real-world data sets - a logbook of the ritual behaviors of a patient with obsessive compulsive disorder and a time series of kill dates from an infamous serial murderer - were examined for non-ergodic properties similar to those found in the synthetic data.


Syphilis Infection during pregnancy: fetal risks and clinical management.
Congenital syphilis is still a cause of perinatal morbidity and mortality. Untreated maternal infection leads to adverse pregnancy outcomes, including early fetal loss, stillbirth, prematurity, low birth weight, neonatal and infant death, and congenital disease among newborns. Clinical manifestations of congenital syphilis are influenced by gestational age, stage of maternal syphilis, maternal treatment, and immunological response of the fetus. It has been traditionally classified in early congenital syphilis and late congenital syphilis. Diagnosis of maternal infection is based on clinical findings, serological tests, and direct identification of treponemes in clinical specimens. Adequate treatment of maternal infection is effective for preventing maternal transmission to the fetus and for treating fetal infection. Prenatal diagnosis of congenital syphilis includes noninvasive and invasive diagnosis. Serological screening during pregnancy and during preconception period should be performed to reduce the incidence of congenital syphilis.


Chemotherapy reduces para-aortic node recurrences in endometrial cancer with positive pelvic and unknown para-aortic nodes.
The objective of this study was to evaluate how the administration of different adjuvant therapies influences the risk for developing recurrences in the para-aortic area in endometrial cancer (EC) with positive pelvic and unknown para-aortic nodes. We retrospectively evaluated the data of 58 patients with EC affected by stage IIIC1 who had undergone pelvic but not para-aortic lymphadenectomy from January 1, 1990 to December 31, 2011. Survival outcomes within the first 5 years after surgery were assessed using the Kaplan-Meier model. Chemotherapy plus radiotherapy, chemotherapy only, and external radiotherapy only were administered in 12 (23%), 18 (34%), and 23 (43%) patients, respectively. Five (9%) patients, who were selected to forego adjuvant therapy due to poor performance status, were excluded from the analysis. Disease-free and overall survivals assessed at 5 years were 54%, and 61%, respectively. All para-aortic recurrences were observed among the patients with endometrioid EC, whereas no cases of para-aortic recurrences were found in patients with nonendometrioid histology (5/36 (14%) vs 0/17 (0%); P = 0.16); the latter were more likely to develop distant (hematogenous, peritoneal, and distant lymphatic) recurrences (P = 0.09). Type of adjuvant therapy was the only factor influencing para-aortic failure: chemotherapy (± radiotherapy) reduced the rate of para-aortic node recurrence in comparison with pelvic radiotherapy as a sole modality (P = 0.01). However, adjuvant therapy did not influence the 5-year survival outcomes (P > 0.05). In the absence of local treatment (ie, para-aortic lymphadenectomy and radiotherapy), the administration of chemotherapy seems effective in reducing recurrences in the para-aortic area among patients with stage IIIC1 endometrioid EC.


Autologus Platelet Rich Fibrin aided Revascularization of an immature, non-vital permanent tooth with apical periodontitis: A case report.
Caries or trauma induced non-vital immature permanent tooth with blunderbuss, thin root which are very common among childrens are corrected using regenerative endodontic (revascularization) procedures. In the presented case, a 16-year-old boy reported with chief complaint of pain in maxillary left central incisor (Tooth #21). Tooth #21 showed grade III mobility, draining labial sinus, and short blunderbuss root with diffuse periapical radiolucency. Patient was explained the treatment plan and written informed consent was taken. Platelet rich fibrin (PRF) was prepared according to standard protocol. Autologous PRF was carried to the apical portion of the root canal after inducing revascularization. Access opening was double sealed with MTA and resin modified glass ionomer cement (RMGI). Baseline, 12 month and 18 month follow-up intraoral radiographs were taken. Clinically case was asymptomatic with complete resolution of intraoral sinus. Periapical healing, apical closure, root lengthening and dentinal wall thickening were uneventful. Thus PRF supplementation hastens the predictability and rate of revascularization in non-vital immature permanent teeth.


Recording and analyzing high-density event-related potentials with infants. Using the Geodesic sensor net.
This article provides an overview of the use of the Geodesic sensor net system for high-density event-related potential (ERP) recording in infants. Some advantages and disadvantages of the system, as applied to infants, are discussed. First, we illustrate that high-density data can be recorded from infants at comparable quality to that observed with conventional (low density) ERP methods. Second, we discuss ways to utilize the greater spatial information available by applying source separation and localization procedures. In particular, we focus on the application of one recent source separation method, Independent Component Analysis (ICA). Finally, we show that source localization can be applied to infant high-density data, although this entails adopting a number of assumptions that remain to be verified. In the future, with improved source separation algorithms, we suggest that single-trial or single-subject analyses may become feasible.


Overestimation of required recovery time during repeated sprint exercise with self-regulated recovery.
This study investigated the reliability and accuracy of self-regulated recovery time and performance during repeated sprinting. On 4 occasions, 14 men (24.5 ± 5.0 years) completed 10 × 6 seconds cycle sprints against 7.5% body mass, self-regulating (SR) recovery time to maintain performance. Subjects then repeated the test, but with a reduced recovery (RR) of 10% less recovery time. Across the first 4 trials, there were no between-trial differences in peak power output (PPO) or mean power output (MPO), recovery time, or fatigue index (p > 0.05). Random variation in recovery time was reduced across trials 3-4 (coefficient of variation [CV] = 7.5%, 95% confidence limits [CL] = 5.4-12.4%) compared with trials 1-2 (CV = 16.0, 95% CL = 11.4-27.0%) and 2-3 (CV = 10.1%, 95% CL = 7.2-16.7%) but was consistent across trials for PPO and MPO (between-trials CV, ≤3.3%). There were no trial effects for any performance, physiological, or perceptual measures when comparing SR with RR (p > 0.05), although heart rate and perceptual measures increased with subsequent sprint efforts (p ≤ 0.05). After 2 familiarization trials, subjects can reliably self-regulate recovery time to maintain performance during repeated sprints. However, subjects overestimate the amount of recovery time required, as reducing this time by 10% had no effect on performance, perceptual, or physiological parameters. Self-regulated sprinting is potentially a reliable training tool, particularly for sprint training where maintenance of work is desired. However, overestimation of required recovery time means that performance improvements may not be achieved if the goal of training is improvement of repeated sprint performance with incomplete recovery.


Bivalirudin or Heparin in Patients Undergoing Invasive Management of Acute Coronary Syndromes.
Contrasting evidence exists on the comparative efficacy and safety of bivalirudin and unfractionated heparin (UFH) in relation to the planned use of glycoprotein IIb/IIIa inhibitors (GPIs). This study assessed the efficacy and safety of bivalirudin compared with UFH with or without GPIs in patients with acute coronary syndrome (ACS) who underwent invasive management. In the MATRIX (Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of AngioX) program, 7,213 patients were randomly assigned to receive either bivalirudin or UFH with or without GPIs at discretion of the operator. The 30-day coprimary outcomes were major adverse cardiovascular events (MACEs) (a composite of death, myocardial infarction, or stroke), and net adverse clinical events (NACEs) (a composite of MACEs or major bleeding). Among 3,603 patients assigned to receive UFH, 781 (21.7%) underwent planned treatment with GPI before coronary intervention. Bailout use of GPIs was similar between the bivalirudin and UFH groups (4.5% and 5.4%) (p = 0.11). At 30 days, the 2 coprimary endpoints of MACEs and NACEs, as well as individual endpoints of mortality, myocardial infarction, stent thrombosis or stroke did not differ among the 3 groups after adjustment. Compared with the UFH and UFH+GPI groups, bivalirudin reduced bleeding, mainly the most severe bleeds, including fatal and nonaccess site-related events, as well as transfusion rates and the need for surgical access site repair. These findings were not influenced by the administered intraprocedural dose of UFH and were confirmed at multiple sensitivity analyses, including the randomly allocated access site. In patients with ACS, the rates of MACEs and NACEs were not significantly lower with bivalirudin than with UFH, irrespective of planned GPI use. However, bivalirudin significantly reduced bleeding complications, mainly those not related to access site, irrespective of planned use of GPIs. (Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of AngioX [MATRIX]; NCT01433627).


Brief Report: The Association of Adverse Childhood Experiences and Suicide-Related Behaviors Among 10th-Grade Secondary School Students.
The association between adverse childhood experiences and suicide-related behaviors (SRB) of adolescents has been widely studied in Western high-income countries, but not yet in Latin America. The aim of this study was to determine this association and to explore a dose-response relationship between adverse childhood experiences and SRB in Chile. We conducted a cross-sectional survey to assess adverse childhood experiences up to 1 year prior to the survey and SRB (suicide ideation and attempts) in a sample of secondary school students. Multilevel and multivariable logistic regressions were run with SRB as dependent and adverse childhood experiences as independent variables, adjusted by self-esteem, general mental health, friend and parental support, and the age at onset of cannabis and alcohol use. We included 7,458 adolescents (48.7% girls), mean age = 16.0 (SD = 0.7), and found a prevalence of 78.1% for at least one adverse childhood experience. The 6-month prevalence of suicidal ideation was 18.1% (95% confidence interval [CI]: 17.2%-19.0%), and the prevalence of suicide attempts was 5.0% (95% CI: 4.6-5.6). Among all adverse childhood experiences, only sexual abuse was a risk factor for both SRB. We also found an independent effect of the total number of adverse childhood experiences on suicidal ideation (p < .001) and on suicide attempts (p < .001). Additionally, ages at onset of alcohol and cannabis use were associated with suicidal ideation and suicidal attempts, respectively. This is the first study exploring the influence of adverse childhood experiences on suicide-related behaviors in adolescents from Latin America.HIGHLIGHTSSexual abuse is associated with suicidal ideation and suicide attempts in 10th-grade secondary school studentsThere is a dose-response effect between adverse childhood experiences and suicide-related behaviorAges at onset of alcohol and cannabis use were associated with suicidal ideation and suicidal attempts, respectively.


Early complications of posterior rod-screw fixation of the cervical and upper thoracic spine.
The technique of rod-screw fixation of the cervical spine is well described. However, there is very little data on the complications incurred by the application of these devices. The purpose of this study was to quantify the risks associated with rod fixation of the cervical spine. A prospective study was performed on 100 consecutive patients treated with this technique. Clinical and radiographic assessment was performed immediately after surgery 3, 6, and 12 months postoperatively, and annually thereafter. The mean follow-up interval was 16.7 months. A total of 888 screws were implanted in 100 patients. Perioperative complications included radiculopathy (n = 4, 0.45% per screw placed), infection and other wound-healing problems (n = 4), screw malposition (n = 2), loss of alignment (n = 1), and cerebrospinal fluid leak (n = 1). There were no examples of spinal cord or vertebral artery injury. Early complications (within 6 mo of surgery) included pseudarthrosis (n = 2) and screw breakage (n = 2, 0.22% per screw placed). There were no late complications. Reoperation was required in eight cases, all within 6 months of the index procedure. Indications for reoperation included wound-healing problems (n = 4), malpositioned screw (n = 2), and pseudarthrosis (n = 2). No patient required another operation for any indication beyond the 6-month postoperative interval. Rod-screw fixation was an effective method of posterior cervical stabilization that could be safely applied in a wide range of spinal disorders. In a complex group of patients, the complication rates were modest, and compared favorably with other methods of fixation.


First Report of Fusarium proliferatum Causing Rot of Garlic Bulbs (Allium sativum) in India.
In September 2009, diseased garlic bulbs (Allium sativum L. cv. Yamuna Safed) were received from producers and exporters in Hyderabad, Andra Pradesh, India. From 2009 to 2010, similar symptoms were observed on stored garlic bulbs (cvs. Yamuna Safed and Agrifound White) in Chittoor, Kadapa, and Hyderabad districts. In some locations, approximately 60% of the garlic bulbs were affected. At first, infected bulbs showed water-soaked, brown spots and then the disease progressed as small, slightly depressed, tan lesions. A total of 120 diseased samples were collected from all localities. Infected tissues were surface sterilized in 1% sodium hypochlorite for 2 min, rinsed three times in sterile distilled water, plated on potato dextrose agar (PDA), and incubated at 25°C for 7 days. Resultant fungal colonies were fast growing with white aerial mycelium and violet to dark pigments. Hyphae were septate and hyaline. Conidiophores were short, simple, or branched. Microconidia were abundant, single celled, oval or club shaped, measuring 4.5 to 10.5 × 1.3 to 2.5 μm, and borne in chains from both mono-and polyphialides. Macroconidia were not produced. On the basis of morphological characteristics, the pathogen was identified as Fusarium proliferatum (Matsushima) Nirenberg (2). Identification was confirmed by amplification of the internal transcribed spacer (ITS) region. Genomic DNA was extracted from pure cultures of an isolate, and the ITS region was amplified using the ITS4/5 primer pair. PCR amplicons of approximately 574 bp were obtained from isolates, and sequence comparisons with GenBank showed 99% similarity with F. proliferatum (Accession No. FN868470.1). Sequence from this study was submitted to GenBank nucleotide database (Accession No. AB646795). Pathogenicity tests were conducted with three isolates of the fungus following the method of Dugan et al. (1). Each assay with an isolate consisted of 10 garlic cloves disinfected in 1% sodium hypochlorite for 45 s, rinsed with sterile distilled water, and injured to a depth of 4 mm with a sterile 1-mm-diameter probe. The wounds were filled with PDA colonized by the appropriate isolate from a 5-day-old culture. Ten cloves for each tested isolate received sterile PDA as a control. The cloves were incubated at 25°C for 5 weeks; tests were repeated once. After 17 days, rot symptoms similar to the original symptoms developed on all inoculated cloves and F. proliferatum was consistently reisolated from symptomatic tissue, fulfilling Koch's postulates. No fungi were recovered from control cloves. F. proliferatum has been reported on garlic in the northwestern United States (1), Serbia (4), and Spain (3). To our knowledge, this is the first report of F. proliferatum causing rot disease on garlic bulbs in India. References: (1) F. M. Dugan et al. Plant Pathol. 52:426, 2003. (2) J. F. Leslie and B. A. Summerell. The Fusarium Laboratory Manual. Blackwell Publishing, Oxford, UK, 2006. (3) D. Palmero et al. Plant Dis. 94:277, 2010. (4) S. Stankovic et al. Eur. J. Plant Pathol. 48:165, 2007.


Ecm1 is a new pre-ribosomal factor involved in pre-60S particle export.
In eukaryotes, ribosome biogenesis is a highly conserved process that starts in the nucleus and ends in the cytoplasm. In actively growing yeast cells, it is estimated that each nuclear pore complex (NPC) contributes to the export of about 25 pre-ribosomal particles per minute. Such an extremely active process requires several redundant export receptors for the pre-60S particles. Here, we report the identification of a novel pre-60S factor, Ecm1, which partially acts like Arx1 and becomes essential when the NPC function is affected. Ecm1 depletion, combined with the deletion of NPC components led to pre-60S retention in the nucleus. Functional links that we identified between Ecm1, 60S biogenesis, pre-60S export, and the NPC were correlated with physical interactions of Ecm1 with pre-60S particles and nucleoporins. These results support that Ecm1 is an additional factor involved in pre-60S export. While Ecm1 and Arx1 have redundant functions, overproduction of either one could not complement the absence of the other, whereas overproduction of Mex67 was able to partially restore the growth defect resulting from the absence of Ecm1 or Arx1. These data highlight the involvement of many factors acting together to export pre-60S particles.


Sex-specific mechanism of social hierarchy in mice.
The establishment of social hierarchies is a naturally occurring, evolutionarily conserved phenomenon with a well-established impact on fitness and health. Investigations of complex social group dynamics may offer novel opportunities for translational studies of autism spectrum disorder. Here we describe a robust behavioral paradigm using an automated version of the tube test. Isogenic groups of male and female mice establish linear social hierarchies that remain highly stable for at least 14 days, the longest interval tested. Remarkably, however, their social strategy is sex-specific: females primarily utilize intrinsic attributes, whereas males are strongly influenced by prior social experience. Using both genetic and pharmacological manipulations, we identify testosterone as a critical sex-specific factor for determining which social strategy is used. Males inheriting a null mutation of the sex-determining region Y (Sry) gene used a similar social cognitive strategy as females. In contrast, females with transgenic expression of Sry utilized a typically male social strategy. Analogously, castration of males and testosterone supplementation of females yielded similar outcomes, with a reversal of their social cognitive strategy. Together, our results demonstrate a sex-specific mechanism underlying social hierarchy, in which both males and females retain the functional capacity to adapt their social strategy. More generally, we expect the automated tube test to provide an important complementary approach for both fundamental and translational studies of social behavior.


Psychological distress at follow-up after major surgery for intra-oral cancer.
A cohort of patients who had received major intra-oral surgery, up to 10 yr (mean 3.5 yr) prior to this study were reviewed and assessed for evidence of current psychological disturbance. Forty-one per cent of patients were found to have significant levels of psychological distress comprising mood disorder, social dysfunction or both types of difficulty. Prevalence of clinical anxiety and depression per se was within the range 22-32%, but few patients were receiving any form of active therapy for these problems. Investigation of predictors revealed that females and younger people were more at risk to psychological distress. Tentative evidence for variability in psychological outcome in relation to tumour site is also reported. Results are discussed with reference to service provision needs and further research priorities.


Comparing linkage designs based on land facets to linkage designs based on focal species.
Least-cost modeling for focal species is the most widely used method for designing conservation corridors and linkages. However, these designs depend on today's land covers, which will be altered by climate change. We recently proposed an alternative approach based on land facets (recurring landscape units of relatively uniform topography and soils). The rationale is that corridors with high continuity of individual land facets will facilitate movement of species associated with each facet today and in the future. Conservation practitioners might like to know whether a linkage design based on land facets is likely to provide continuity of modeled breeding habitat for species needing connectivity today, and whether a linkage for focal species provides continuity and interspersion of land facets. To address these questions, we compared linkages designed for focal species and land facets in three landscapes in Arizona, USA. We used two variables to measure linkage utility, namely distances between patches of modeled breeding habitat for 5-16 focal species in each linkage, and resistance profiles for focal species and land facets between patches connected by the linkage. Compared to focal species designs, linkage designs based on land facets provided as much or more modeled habitat connectivity for 25 of 28 species-landscape combinations, failing only for the three species with the most narrowly distributed habitat. Compared to land facets designs, focal species linkages provided lower connectivity for about half the land facets in two landscapes. In areas where a focal species approach to linkage design is not possible, our results suggest that conservation practitioners may be able to implement a land facets approach with some confidence that the linkage design would serve most potential focal species. In areas where focal species designs are possible, we recommend using the land facet approach to complement, rather than replace, focal species approaches.


Comparison of bioabsorbable pins and Kirschner wires in the fixation of chevron osteotomies for hallux valgus.
A retrospective review of the medical records and radiographs of 32 consecutive patients, totaling 52 extremities with chevron osteotomies for hallux valgus, was conducted to compare K wire fixation with absorbable (poly-p-dioxanone) pin fixation. Each group comprised 21 feet, with a mean clinical follow-up of 35.6 months (25.6-50.5 months) in the K wire group and 23.1 months (13.7-28.8 months) in the absorbable pin group. Demographics as well as final clinical follow-up scores (hallux-metatarsophalangeal-interphalangeal scale and visual analogue scores) were similar in both groups. Postoperative hallux valgus and intermetatarsal angles were similar in both groups. No complications, such as osteolysis for inflammatory sinus formation, occurred in the absorbable pin group. Two patients in the K wire group had a malunited osteotomy and two patients had a retained K wire at final follow-up. Our experience suggests that poly-p-dioxanone pins are at least as effective as K wires, and the previous reports of inflammatory sinus formation and osteolysis are not a significant concern in the fixation of chevron osteotomies for hallux valgus.


Evaluation of reticulocyte counts by flow cytometry in a routine laboratory.
Reticulocyte counting using flow cytometry and a membrane-permeable fluorescent dye, thiazole orange, was evaluated as an alternative to the conventional manual method. The flow cytometric method was more precise (mean c.v. of 4.3%) than the imprecise manual technique (mean c.v. of 22.4%). Linearity was highly acceptable (r = 0.99) over the reticulocyte count range of 1.8-30.1%. Flow cytometry allows processing of large numbers of samples with reduction in technologist time, and the improved precision and tenfold increase in the number of cells counted should considerably improve the clinical utility of the reticulocyte count.


Role of hoogsteen edge hydrogen bonding at template purines in nucleotide incorporation by human DNA polymerase iota.
Human DNA polymerase iota (Pol iota) differs from other DNA polymerases in that it exhibits a marked template specificity, being more efficient and accurate opposite template purines than opposite pyrimidines. The crystal structures of Pol iota with template A and incoming dTTP and with template G and incoming dCTP have revealed that in the Pol iota active site, the templating purine adopts a syn conformation and forms a Hoogsteen base pair with the incoming pyrimidine which remains in the anti conformation. By using 2-aminopurine and purine as the templating residues, which retain the normal N7 position but lack the N(6) of an A or the O(6) of a G, here we provide evidence that whereas hydrogen bonding at N(6) is dispensable for the proficient incorporation of a T opposite template A, hydrogen bonding at O(6) is a prerequisite for C incorporation opposite template G. To further analyze the contributions of O(6) and N7 hydrogen bonding to DNA synthesis by Pol iota, we have examined its proficiency for replicating through the (6)O-methyl guanine and 8-oxoguanine lesions, which affect the O(6) and N7 positions of template G, respectively. We conclude from these studies that for proficient T incorporation opposite template A, only the N7 hydrogen bonding is required, but for proficient C incorporation opposite template G, hydrogen bonding at both the N7 and O(6) is an imperative. The dispensability of N(6) hydrogen bonding for proficient T incorporation opposite template A has important biological implications, as that would endow Pol iota with the ability to replicate through lesions which impair the Watson-Crick hydrogen bonding potential at both the N1 and N(6) positions of templating A.


Coordination Elicits Synchronous Brain Activity Between Co-actors: Frequency Ratio Matters.
People could behave in two different ways when engaging in interpersonal coordination activities: moving at the same frequency (isofrequency pattern, IP; the movement frequency ratio is 1:1) or at different frequencies (multifrequency pattern, MP; the movement frequency ratio is non 1:1). However, how the interpersonal coordination pattern modulates coordination outcome and the related brain-to-brain connectivity is not fully understood. Here, we adopted a continuous joint drawing task in which two participants co-drew parallelogram shapes according to two coordination patterns (i.e., IP vs. MP) while their brain activities were simultaneously recorded by the functional near-infrared spectroscopy (fNIRS) based hyperscanning technique. Dyads showed better coordination performance, as well as relatively greater interpersonal brain synchronization (IBS) at the left frontopolar area, in the MP condition compared to the IP condition. Granger causality analyses further disclosed the bidirectional influences between the brains of the coordinating individuals. Such interpersonal influences were enhanced when individuals coordinated in the MP condition. Finally, the IBS during coordination was related to the dyadic self-control level. Taken together, our study revealed that interpersonal multifrequency coordination pattern facilitates the coordination efficiency, which was associated with the enhanced brain-to-brain connectivity. Our work also suggests the potentially positive role of self-control during the interpersonal coordination process.


Endocytosis of PEGylated agents enhances cancer imaging and anticancer efficacy.
PEGylated nanoparticles and macromolecules are increasingly used in cancer imaging and anticancer treatment. The role of receptor-mediated endocytosis in the efficacy of these agents, however, has not been clearly defined. Here, we developed a matched pair of endocytic and nonendocytic receptors to directly and unambiguously assess this issue. The ligand-binding domains of the low-density lipoprotein receptor (LDLR) or a truncated LDLR lacking the NPXY endocytosis motif (DeltaLDLR) were replaced with an anti-polyethylene glycol antibody (alphaPEG) to form endocytic alphaPEG-LDLR and nonendocytic alphaPEG-DeltaLDLR receptors. The receptors were stably expressed at similar levels on the surface of HCC36 cells. HCC36/alphaPEG-LDLR cells, but not HCC36/alphaPEG-DeltaLDLR cells, rapidly endocytosed PEG-quantum dots and PEG-liposomal doxorubicin (Lipo-Dox) in vitro and in vivo. Lipo-Dox was significantly more cytotoxic to HCC36/alphaPEG-LDLR cells than to HCC36/alphaPEG-DeltaLDLR cells. HCC36/alphaPEG-LDLR tumors also accumulated significantly more PEGylated near-IR probes (PEG-NIR797) and PEG-liposomal-(111)In than HCC36/alphaPEG-DeltaLDLR tumors in vivo. Furthermore, Lipo-Dox more significantly suppressed the growth of established HCC36/alphaPEG-LDLR tumors as compared with HCC36/alphaPEG-DeltaLDLR tumors. Our data show that endocytosis of PEGylated probes and drugs enhances both cancer imaging and anticancer efficacy, indicating that endocytic receptors are superior targets for the design of cancer imaging probes and immunoliposomal drugs.


ACG Clinical Guideline: Upper Gastrointestinal and Ulcer Bleeding.
We performed systematic reviews addressing predefined clinical questions to develop recommendations with the GRADE approach regarding management of patients with overt upper gastrointestinal bleeding. We suggest risk assessment in the emergency department to identify very-low-risk patients (e.g., Glasgow-Blatchford score = 0-1) who may be discharged with outpatient follow-up. For patients hospitalized with upper gastrointestinal bleeding, we suggest red blood cell transfusion at a threshold of 7 g/dL. Erythromycin infusion is suggested before endoscopy, and endoscopy is suggested within 24 hours after presentation. Endoscopic therapy is recommended for ulcers with active spurting or oozing and for nonbleeding visible vessels. Endoscopic therapy with bipolar electrocoagulation, heater probe, and absolute ethanol injection is recommended, and low- to very-low-quality evidence also supports clips, argon plasma coagulation, and soft monopolar electrocoagulation; hemostatic powder spray TC-325 is suggested for actively bleeding ulcers and over-the-scope clips for recurrent ulcer bleeding after previous successful hemostasis. After endoscopic hemostasis, high-dose proton pump inhibitor therapy is recommended continuously or intermittently for 3 days, followed by twice-daily oral proton pump inhibitor for the first 2 weeks of therapy after endoscopy. Repeat endoscopy is suggested for recurrent bleeding, and if endoscopic therapy fails, transcatheter embolization is suggested.


Long-term repetition priming in spoken and written word production: evidence for a contribution of phonology to handwriting.
Although it is relatively well established that access to orthographic codes in production tasks is possible via an autonomous link between meaning and spelling (e.g., Rapp, Benzing, & Caramazza, 1997), the relative contribution of phonology to orthographic access remains unclear. Two experiments demonstrated persistent repetition priming in spoken and written single-word responses, respectively. Two further experiments showed priming from spoken to written responses and vice versa, which is interpreted as reflecting a role of phonology in constraining orthographic access. A final experiment showed priming from spoken onto written responses even when participants engaged in articulatory suppression during writing. Overall, the results support the view that access to orthography codes is accomplished via both the autonomous link between meaning and spelling and an indirect route via phonology.


The neuronal control of dragonfly flight. I. Anatomy.
The mechanical action and innervation of the major flight muscles of dragonflies are described. All flight muscles investigated are innervated by at least 3 motor neurones and one by as many as 15. Cell bodies of motor neurones that innervate the same muscle are clustered together and have similar, widespread dendritic branching patterns. Motor neurones of leg muscles have greater variety in cell body size and position than the major flight motor neurones. Striking similarities between the positions of cell bodies of motor neurones in dragonflies and the positions of homologous motor neurones in other insects raise interesting questions about the evolution of insect nervous systems.


A global protein kinase and phosphatase interaction network in yeast.
The interactions of protein kinases and phosphatases with their regulatory subunits and substrates underpin cellular regulation. We identified a kinase and phosphatase interaction (KPI) network of 1844 interactions in budding yeast by mass spectrometric analysis of protein complexes. The KPI network contained many dense local regions of interactions that suggested new functions. Notably, the cell cycle phosphatase Cdc14 associated with multiple kinases that revealed roles for Cdc14 in mitogen-activated protein kinase signaling, the DNA damage response, and metabolism, whereas interactions of the target of rapamycin complex 1 (TORC1) uncovered new effector kinases in nitrogen and carbon metabolism. An extensive backbone of kinase-kinase interactions cross-connects the proteome and may serve to coordinate diverse cellular responses.


Predictors of IMRT and conformal radiotherapy use in head and neck squamous cell carcinoma: a SEER-Medicare analysis.
The extent to which new techniques for the delivery of radiotherapy for head and neck squamous cell carcinoma (HNSCC) have diffused into clinical practice is unclear, including the use of 3-dimensional conformal RT (3D-RT) and intensity-modulated radiation therapy (IMRT). Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database, we identified 2,495 Medicare patients with Stage I-IVB HNSCC diagnosed at age 65 years or older between 2000 and 2005 and treated with either definitive (80%) or adjuvant (20%) radiotherapy. Our primary aim was to analyze the trends and predictors of IMRT use over this time, and the secondary aim was a similar description of the trends and predictors of conformal radiotherapy (CRT) use, defined as treatment with either 3D-RT or IMRT. Three hundred sixty-four (15%) patients were treated with IMRT, and 1,190 patients (48%) were treated with 3D-RT. Claims for IMRT and CRT rose from 0% to 33% and 39% to 86%, respectively, between 2000 and 2005. On multivariable analysis, IMRT use was associated with SEER region (West 18%; Northeast 11%; South 12%; Midwest 13%), advanced stage (advanced, 21%; early, 9%), non-larynx site (non-larynx, 23%; larynx, 7%), higher median census tract income (highest vs. lowest quartile, 18% vs. 10%), treatment year (2003-2005, 31%; 2000-2002, 6%), use of chemotherapy (26% with; 9% without), and higher radiation oncologist treatment volume (highest vs. lowest tertile, 23% vs. 8%). With CRT as the outcome, only SEER region, treatment year, use of chemotherapy, and increasing radiation oncologist HNSCC volume were significant on multivariable analysis. The use of IMRT and CRT by Medicare beneficiaries with HNSCC rose significantly between 2000 and 2005 and was associated with both clinical and non-clinical factors, with treatment era and radiation oncologist HNSCC treatment volume serving as the strongest predictors of IMRT use.


A comparative analysis of case presentation modalities used in clinical reasoning coursework in occupational therapy.
This study used mixed methods to compare four different styles of case presentation in a course designed to develop the clinical reasoning skills of master's level occupational therapy students. Modalities used to present cases were printed text, videotape, live interview, and CD-ROM movies delivered on an Internet platform. The researchers sought to determine the relative merits and limitations of each modality from both pedagogical and practical standpoints. Results indicate that the choice of modality does not compromise the ability of students to meet learning objectives related to clinical reasoning; however, several advantages and disadvantages with respect to practical aspects of presentation and learning were identified from instructor and student perspectives. The strength of the overall instructional format, and decisions concerning the amount and type of information provided in the cases were found to be more relevant to the quality of the learning experience than the modality of presentation. Recommendations are provided for structuring clinical reasoning learning experiences that combine the best features from the case modalities examined in this study.


Intakes of alcohol and folate during adolescence and risk of proliferative benign breast disease.
To examine the combined effect of alcohol and folate intake during adolescence on the risk of proliferative benign breast disease (BBD). We used data from 29 117 women in the Nurses' Health Study II who completed both adolescent alcohol consumption questions in 1989 and an adolescent diet questionnaire in 1998. A total of 659 women with proliferative BBD diagnosed between 1991 and 2001 were confirmed by central pathology review. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals (CIs), adjusted for established risk factors of breast cancer. Adolescent alcohol consumption was dose-dependently associated with an increased risk of proliferative BBD (hazard ratio = 1.15 per 10 g/day consumption; 95% CI, 1.03-1.28). There was no significant association between adolescent folate intake and the risk of proliferative BBD. Stratified analyses showed that each 10-g/day alcohol intake during adolescence was associated with a 21% (95% CI, 1.01-1.45) increase in the risk of proliferative BBD among women with low folate intake during adolescence, which was not significantly different from the alcohol-associated risk among women with moderate and high folate intake during adolescence (P for interaction = 0.18). Adolescent alcohol consumption is associated with increased risk of proliferative BBD, which may not be reduced by increased folate intake during adolescence.


The smart-talk trap.
In today's business world, there's no shortage of know-how. When companies get into trouble, their executives have vast resources at their disposal: their own experiences, colleagues' ideas, reams of computer-generated data, thousands of publications, and consultants armed with the latest managerial concepts and tools. But all too often, even with all that knowledge floating around, companies are plagued with an inertia that comes from knowing too much and doing too little--a phenomenon the authors call the knowing-doing gap. The gap often can be traced to a basic human propensity: the willingness to let talk substitute for action. When confronted with a problem, people act as though discussing it, formulating decisions, and hashing out plans for action are the same as actually fixing it. And after researching organizations of all shapes and sizes, the authors concluded that a particular kind of talk is an especially insidious inhibitor of action: "smart talk." People who can engage in such talk generally sound confident and articulate; they can spout facts and may even have interesting ideas. But such people often exhibit the less benign aspects of smart talk as well: They focus on the negative, and they favor unnecessarily complex or abstract language. The former lapses into criticism for criticism's sake; the latter confuses people. Both tendencies can stop action in its tracks. How can you shut the smart-talk trap and close the knowing-doing gap? The authors lay out five methods that successful companies employ in order to translate the right kind of talk into intelligent action.


Long form of latent TGF-beta binding protein 1 (Ltbp1L) is essential for cardiac outflow tract septation and remodeling.
Latent TGF-beta binding protein 1 (LTBP1) is a member of the LTBP/fibrillin family of extracellular proteins. Due to the usage of different promoters, LTBP1 exists in two major forms, long (L) and short (S), each expressed in a temporally and spatially unique fashion. Both LTBP1 molecules covalently interact with latent TGF-beta and regulate its function, presumably via interaction with the extracellular matrix (ECM). To explore the in vivo role of Ltbp1 in mouse development, at the time when only the L isoform is expressed, we mutated the Ltbp1L locus by gene targeting. Ltbp1L-null animals die shortly after birth from defects in heart development, consisting of the improper septation of the cardiac outflow tract (OFT) and remodeling of the associated vessels. These cardiac anomalies present as persistent truncus arteriosus (PTA) and interrupted aortic arch (IAA), which are associated with the faulty function of cardiac neural crest cells (CNCCs). The lack of Ltbp1L in the ECM of the septating OFT and associated vessels results in altered gene expression and function of CNCCs and decreased Tgf-beta activity in the OFT. This phenotype reveals a crucial role for Ltbp1L and matrix as extracellular regulators of Tgf-beta activity in heart organogenesis.


Leptomeningeal metastasis from non-small cell lung cancer: survival and the impact of whole brain radiotherapy.
Leptomeningeal metastasis (LM), or leptomeningeal carcinomatosis, is a devastating complication of non-small cell lung cancer (NSCLC), and the optimal therapeutic approach remains challenging. A retrospective review was carried out to assess the impact of whole brain radiotherapy (WBRT), intrathecal therapy (IT), and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) on outcomes. Patients with newly diagnosed LM from NSCLC from January 2002 to December 2009 were identified through institutional databases and medical records reviewed. Survival was assessed by Kaplan-Meier and landmark analyses by administered treatment to minimize selection bias. We identified 125 patients (45 men, 80 women) with LM from NSCLC, median age 59 years (range, 28-87 years). Almost all (123 [98%]) patients have died and median overall survival was 3.0 months (95% confidence interval, 2.0-4.0). No differences in survival were seen between patients who were treated with WBRT (n =46) and those who were not (n =59, p =0.84) in a landmark analysis. In the seven patients selected to receive IT chemotherapy, median survival was 18 months (range, 5-33 months) and appeared superior to those not selected for this treatment (p =0.001) in a landmark analysis. The median survival of the nine patients with known EGFR mutations (all of whom received TKIs at some point) was 14 months (range, 1-28 months). This retrospective study, the largest published series, demonstrates the poor survival of LM from NSCLC. In this study, survival was not improved by WBRT. The survival of patients selected for IT chemotherapy and those with EGFR mutations treated with TKIs highlights the importance of developing novel agents.


Predominant pathogens in hospital infections.
To determine the distribution of pathogens causing nosocomial infections in United States hospitals, we analysed data from the National Nosocomial Infections Surveillance (NNIS) System. From October 1986 to December 1990, amongst hospitals conducting hospital-wide surveillance, the five most commonly reported pathogens were Escherichia coli (13.7%), Staphylococcus aureus (11.2%), enterococci (10.7%), Pseudomonas aeruginosa (10.1%), and coagulase-negative staphylococci (9.7%). The commonest pathogens reported by site included, bloodstream: coagulase-negative staphylococci, S. aureus, enterococci, E. coli, and Candida spp.; lower respiratory tract infection: S. aureus, P. aeruginosa and Enterobacter spp.; surgical wound infection: S. aureus, enterococci and coagulase-negative staphylococci; and urinary tract infection: E. coli, enterococci, and P. aeruginosa. Among hospitals conducting intensive care unit (ICU) surveillance, the commonest pathogens were P. aeruginosa (12.4%), S. aureus (12.3%), coagulase-negative staphylococci (10.2%), Candida spp. (10.1%), Enterobacter spp. and enterococci (8.6% each). In the ICUs, the commonest pathogens found in the bloodstream were coagulase-negative staphylococci, S. aureus, and enterococci; in lower respiratory tract infections P. aeruginosa, S. aureus, and enterococci; in surgical wound infections enterococci, coagulase-negative staphylococci, and Enterobacter spp. and in urinary tract infections Candida spp., E. coli, enterococci, P. aeruginosa, and Enterobacter spp. These data show that S. aureus, E. coli and P. aeruginosa remain important nosocomial pathogens, that coagulase-negative staphylococci, enterococci and C. albicans are pathogens of increasing importance, and that the distribution of pathogens differs by site and hospital location.


A comparison of costs associated with endoscope-assisted craniectomy versus open cranial vault repair for infants with sagittal synostosis.
The surgical management of infants with sagittal synostosis has traditionally relied on open cranial vault remodeling (CVR) techniques; however, minimally invasive technologies, including endoscope-assisted craniectomy (EAC) repair followed by helmet therapy (HT, EAC+HT), is increasingly used to treat various forms of craniosynostosis during the 1st year of life. In this study the authors determined the costs associated with EAC+HT in comparison with those for CVR. The authors performed a retrospective case-control analysis of 21 children who had undergone CVR and 21 who had undergone EAC+HT. Eligibility criteria included an age less than 1 year and at least 1 year of clinical follow-up data. Financial and clinical records were reviewed for data related to length of hospital stay and transfusion rates as well as costs associated with physician, hospital, and outpatient clinic visits. The average age of patients who underwent CVR was 6.8 months compared with 3.1 months for those who underwent EAC+HT. Patients who underwent EAC+HT most often required the use of 2 helmets (76.5%), infrequently required a third helmet (13.3%), and averaged 1.8 clinic visits in the first 90 days after surgery. Endoscope-assisted craniectomy plus HT was associated with shorter hospital stays (mean 1.10 vs 4.67 days for CVR, p < 0.0001), a decreased rate of blood transfusions (9.5% vs 100% for CVR, p < 0.0001), and a decreased operative time (81.1 vs 165.8 minutes for CVR, p < 0.0001). The overall cost of EAC+HT, accounting for hospital charges, professional and helmet fees, and clinic visits, was also lower than that of CVR ($37,255.99 vs $56,990.46, respectively, p < 0.0001). Endoscope-assisted craniectomy plus HT is a less costly surgical option for patients than CVR. In addition, EAC+HT was associated with a lower utilization of perioperative resources. Theses findings suggest that EAC+HT for infants with sagittal synostosis may be a cost-effective first-line surgical option.


Global Identification of the Full-Length Transcripts and Alternative Splicing Related to Phenolic Acid Biosynthetic Genes in Salvia miltiorrhiza.
Salvianolic acids are among the main bioactive components in Salvia miltiorrhiza, and their biosynthesis has attracted widespread interest. However, previous studies on the biosynthesis of phenolic acids using next-generation sequencing platforms are limited with regard to the assembly of full-length transcripts. Based on hybrid-seq (next-generation and single molecular real-time sequencing) of the S. miltiorrhiza root transcriptome, we experimentally identified 15 full-length transcripts and four alternative splicing events of enzyme-coding genes involved in the biosynthesis of rosmarinic acid. Moreover, we herein demonstrate that lithospermic acid B accumulates in the phloem and xylem of roots, in agreement with the expression patterns of the identified key genes related to rosmarinic acid biosynthesis. According to co-expression patterns, we predicted that six candidate cytochrome P450s and five candidate laccases participate in the salvianolic acid pathway. Our results provide a valuable resource for further investigation into the synthetic biology of phenolic acids in S. miltiorrhiza.


Nutritional physiology of life-history trade-offs: how food protein-carbohydrate content influences life-history traits in the wing-polymorphic cricket Gryllus firmus.
Although life-history trade-offs result from the differential acquisition and allocation of nutritional resources to competing physiological functions, many aspects of this topic remain poorly understood. Wing-polymorphic insects, which possess alternative morphs that trade off allocation to flight capability versus early reproduction, provide a good model system for exploring this topic. In this study, we used the wing-polymorphic cricket Gryllus firmus to test how expression of the flight capability versus reproduction trade-off was modified across a heterogeneous protein-carbohydrate nutritional landscape. Newly molted adult female long- and short-winged crickets were given one of 13 diets with different concentrations and ratios of protein and digestible carbohydrate; for each cricket, we measured consumption patterns, growth and allocation to reproduction (ovary mass) versus flight muscle maintenance (flight muscle mass and somatic lipid stores). Feeding responses in both morphs were influenced more by total macronutrient concentration than by protein-carbohydrate ratio, except at high-macronutrient concentration, where protein-carbohydrate balance was important. Mass gain tended to be greatest on protein-biased diets for both morphs, but was consistently lower across all diets for long-winged females. When long-winged females were fed high-carbohydrate foods, they accumulated greater somatic lipid stores; on high-protein foods, they accumulated greater somatic protein stores. Food protein-carbohydrate content also affected short-winged females (selected for early reproductive onset), which showed dramatic increases in ovary size, including ovarian stores of lipid and protein, on protein-biased foods. This is the first study to show how the concentration and ratio of dietary protein and carbohydrate affects consumption and allocation to key physiological features associated with the reproduction-dispersal life-history trade-off.


Transcranial Magnetic Stimulation: A Clinical Primer for Nonexperts.
Transcranial magnetic stimulation (TMS) is a safe and effective therapeutic modality for a rapidly expanding range of neuropsychiatric indications. Among psychiatric conditions, it is presently approved by the US Food and Drug Administration for treatment-resistant unipolar major depressive disorder and obsessive-compulsive disorder, 2 highly prevalent conditions with a considerable public health impact. There is also mounting evidence for its clinical utility in numerous other neuropsychiatric conditions. Nonetheless, many mental health providers, as well as primary care and other providers, remain unfamiliar with its clinical use. In this primer, we seek to describe in nontechnical terms how the magnetic field is applied to the brain, the unmet needs that may be remediated with TMS, the present state of evidence for clinical effectiveness, particularly in major depressive disorder, the safety profile of TMS, what patients experience during TMS, and some recent developments that serve to advance the use of this still novel intervention. TMS is poised to assume an important place in the armamentarium of interventions to better serve our patients, especially those with serious, chronic conditions with high rates of resistance to more conventional treatments. Consequently, it is essential that mental health providers gain as adequate a working knowledge of device-based interventions such as TMS as they currently have of psychopharmacological and psychosocial interventions. Among other potential benefits, this information should aid the process of obtaining informed consent from patients who are candidates for these treatments.


Infant and child deaths in acute care settings: implications for palliative care.
Despite 56% of child deaths occurring in inpatient hospital settings, who these children are and how they die has not been fully described. The purpose of this study was to identify the characteristics of those infants and children who die in acute care settings, and describe the extent to which palliative care was used prior to their deaths. This study used a retrospective descriptive design. The 2000 Healthcare Cost and Utilization Project (HCUP) Kids' Inpatient Database (KID) was analyzed to define the national population of infants and children who die in acute care settings. In addition, medical records of a random sample of deaths at a large academic children's hospital were reviewed to further characterize the events surrounding childhood deaths. The 2000 HCUP-KID included 13,643 deaths of children less than 18 years of age, representing an estimated 26,571 infant and child deaths, nationally. One hundred eleven infants and children who died at an academic children's hospital over four years were included in a detailed chart review. The majority of the deaths in both databases occurred in males, whites, and infants less than 12 months of age. Of the children who died in the academic children's hospital, most died in a critical care unit (86%). Fifty-four percent of the HCUP-KID deaths occurred in general hospitals and 46% occurred in children's hospitals. Children who died in children's hospitals had more complex chronic conditions (CCC) than in general hospitals. Regardless of hospital type, the most prevalent CCC categories were neuromuscular, cardiovascular, respiratory, congenital/genetic, and malignancies. The results of this study suggest that large numbers of children die in both general and children's hospitals with a wide variety of illnesses and at all ages, indicating that all acute care pediatric providers need a working knowledge of and access to end-of-life and palliative care services.


Disseminated phaeohyphomycosis in weedy seadragons (Phyllopteryx taeniolatus) and leafy seadragons (Phycodurus eques) caused by species of Exophiala, including a novel species.
During the period from January 2002 to March 2007, infections by melanized fungi were identified with greater frequency in aquarium-maintained leafy seadragons (Phycodurus eques) and weedy seadragons (Phyllopteryx taeniolatus), pivotal species to the educational and environmental concerns of the aquarium industry and conservation groups. The objective of this study was to characterize the pathology and identify fungi associated with phaeohyphomycotic lesions in these species. Samples from 14 weedy and 6 leafy seadragons were received from 2 institutions and included fresh, frozen, and formalin-fixed tissues from necropsy and biopsy specimens. Fresh and frozen tissues were cultured for fungi on Sabouraud dextrose agar only or both Sabouraud dextrose agar and inhibitory mold agar with gentamicin and chloramphenicol at 30 degrees C. Isolates were processed for morphologic identification and molecular sequence analysis of the internal transcribed spacer region and D1/D2 domains of the large subunit ribosomal RNA gene. Lesions were extensive and consisted of parenchymal and vascular necrosis with fungal invasion of gill (11/20), kidney (14/20), and other coelomic viscera with or without cutaneous ulceration (13/20). Exophiala sp. isolates were obtained from 4 weedy and 3 leafy seadragons and were identified to species level in 6 of 7 instances, namely Exophiala angulospora (1) and a novel species of Exophiala (5), based on nucleotide sequence comparisons and phylogenetic analyses. Disseminated phaeohyphomycosis represents an important pathologic condition of both weedy and leafy seadragons for which 2 species of Exophiala, 1 a novel species, have been isolated.


Continuity in intuition and insight: from real to naturalistic virtual environment.
Intuition and insight can be deployed on the same continuum. Intuition is the unconscious ability to create links between information; insight is a process by which a sudden comprehension and resolution of a situation arises (i.e. euréka). In the present study, real and virtual environments were used to trigger intuition and insight. The study hypothesised that immersion in real primed environments would facilitate the emergence of intuition and insight in a virtual environment. Forty nine healthy participants were randomly assigned to two groups: "primed" and "non primed." "Primed" participants were immersed in a real environment with olfactory and visual cues; "non primed" participants did not receive any cues. All participants were exposed to a 3D naturalistic virtual environment which represented a district in Paris via a Head Mounted Display (HMD). Locations presented in the virtual scene (i.e. café places) were related to both olfactory and visual primes (i.e. café) and were based on the continuity between real and virtual environments. Once immersed in the virtual environment, all participants were instructed to use their intuition to envision the selected locations during which Skin Conductance Responses (SCRs) and verbal declarations were recorded. When initiation (a) and immersion (b) phases in the virtual environment were considered, "primed" participants had higher SCRs during the immersion phase than the initiation phase in the virtual environment. They showed higher SRCs during the first part of the virtual immersion than "non primed" participants. During the phenomenological interview, "primed" participants reported a higher number of correct intuitive answers than "non primed" participants. Moreover, "primed" participants "with" insight had higher SCRs during real environment immersion than "primed" participants "without" insight. The findings are consistent with the idea that intuitive decisions in various tasks are based on the activation of pre-existing knowledge, which is unconsciously retrieved, but nevertheless can elicit an intuitive impression of coherence and can generate insight.


Spatial and temporal patterns of neutral and adaptive genetic variation in the endangered African wild dog (Lycaon pictus).
Deciphering patterns of genetic variation within a species is essential for understanding population structure, local adaptation and differences in diversity between populations. Whilst neutrally evolving genetic markers can be used to elucidate demographic processes and genetic structure, they are not subject to selection and therefore are not informative about patterns of adaptive variation. As such, assessments of pertinent adaptive loci, such as the immunity genes of the major histocompatibility complex (MHC), are increasingly being incorporated into genetic studies. In this study, we combined neutral (microsatellite, mtDNA) and adaptive (MHC class II DLA-DRB1 locus) markers to elucidate the factors influencing patterns of genetic variation in the African wild dog (Lycaon pictus); an endangered canid that has suffered extensive declines in distribution and abundance. Our genetic analyses found all extant wild dog populations to be relatively small (N(e) < 30). Furthermore, through coalescent modelling, we detected a genetic signature of a recent and substantial demographic decline, which correlates with human expansion, but contrasts with findings in some other African mammals. We found strong structuring of wild dog populations, indicating the negative influence of extensive habitat fragmentation and loss of gene flow between habitat patches. Across populations, we found that the spatial and temporal structure of microsatellite diversity and MHC diversity were correlated and strongly influenced by demographic stability and population size, indicating the effects of genetic drift in these small populations. Despite this correlation, we detected signatures of selection at the MHC, implying that selection has not been completely overwhelmed by genetic drift.


Quality of life in MAP.3 (Mammary Prevention 3): a randomized, placebo-controlled trial evaluating exemestane for prevention of breast cancer.
Exemestane, a steroidal aromatase inhibitor, reduced invasive breast cancer incidence by 65% among 4,560 postmenopausal women randomly assigned to exemestane (25 mg per day) compared with placebo in the National Cancer Institute of Canada (NCIC) Clinical Trials Group MAP.3 (Mammary Prevention 3) trial, but effects on quality of life (QOL) were not fully described. Menopause-specific and health-related QOL were assessed by using the four Menopause-Specific Quality of Life Questionnaire (MENQOL) domains and the eight Medical Outcomes Study Short Form Health Survey (SF-36) scales at baseline, 6 months, and yearly thereafter. MENQOL questionnaire completion was high (88% to 98%) in both groups at each follow-up visit. Change scores for each MENQOL and SF-36 scale, calculated at each assessment time relative to baseline, were compared by using the Wilcoxon rank-sum test. Clinically important worsened QOL was defined as a MENQOL change score increase of more than 0.5 (of 8) points and an SF-36 change score decrease of more than 5 (of 100) points from baseline. Exemestane had small negative effects on women's self-reported vasomotor symptoms, sexual symptoms, and pain, which occurred mainly in the first 6 months to 2 years after random assignment. However, these changes represented only a small excess number of women being given exemestane with clinically important worsening of QOL at one time or another; specifically, 8% more in the vasomotor domain and 4% more each in the sexual domain and for pain. No other between-group differences were observed. Overall, slightly more women in the exemestane arm (32%) than in the placebo arm (28%) discontinued assigned treatment. Exemestane given for prevention has limited negative impact on menopause-specific and health-related QOL in healthy postmenopausal women at risk for breast cancer.


Identification of a gag-encoded cytotoxic T-lymphocyte epitope from FBL-3 leukemia shared by Friend, Moloney, and Rauscher murine leukemia virus-induced tumors.
FBL-3 is a highly immunogenic murine leukemia of C57BL/6 origin induced by Friend murine leukemia virus (MuLV). Immunization of C57BL/6 mice with FBL-3 readily elicits CD8+ cytotoxic T lymphocytes (CTL) capable of lysing FBL-3 as well as syngeneic leukemias induced by Moloney and Rauscher MuLV. The aim of this current study was to identify the immunogenic epitope(s) recognized by the FBL-3-specific CD8+ CTL. A series of FBL-3-specific CD8+ CTL clones were generated from C57BL/6 mice immunized to FBL-3. The majority of CTL clones (32 of 38) were specific for F-MuLV gag-encoded antigen. By using a series of recombinant vaccinia viruses expressing full-length and truncated F-MuLV gag genes, the antigenic epitope recognized by the FBL-3 gag-specific CTL clones, as well as by bulk-cultured CTL from spleens of mice immune to FBL-3, was localized to the leader sequence of gPr80gag protein. The precise amino acid sequence of the CTL epitope in the leader sequence was identified as CCLCLTVFL (positions 85-93) by examining lysis of targets incubated with a series of synthetic leader sequence peptides. No evidence of other CTL epitopes in the gPr80gag or Pr65gag core virion structural polyproteins was found. The identity of CCLCLTVFL as the target peptide was validated by showing that immunization with the peptide elicited CTL that lysed FBL-3. The CTL elicited by the Gag peptide also specifically lysed syngeneic leukemia cells induced by Moloney and Rauscher MuLV (MBL-2 and RBL-5). The transmembrane peptide was shown to be the major gag-encoded antigenic epitope recognized by bulk-cultured CTL derived from C57BL/6 mice immunized to MBL-2 or RBL-5. Thus, the CTL epitope of FBL-3 is localized to the transmembrane anchor domain of the nonstructural Gag polyprotein and is shared by leukemia/lymphoma cell lines induced by Friend, Moloney, and Rauscher MuLV.


High resolution three-dimensional photoacoutic tomography with CCD-camera based ultrasound detection.
A photoacoustic tomograph based on optical ultrasound detection is demonstrated, which is capable of high resolution real-time projection imaging and fast three-dimensional (3D) imaging. Snapshots of the pressure field outside the imaged object are taken at defined delay times after photoacoustic excitation by use of a charge coupled device (CCD) camera in combination with an optical phase contrast method. From the obtained wave patterns photoacoustic projection images are reconstructed using a back propagation Fourier domain reconstruction algorithm. Applying the inverse Radon transform to a set of projections recorded over a half rotation of the sample provides 3D photoacoustic tomography images in less than one minute with a resolution below 100 µm. The sensitivity of the device was experimentally determined to be 5.1 kPa over a projection length of 1 mm. In vivo images of the vasculature of a mouse demonstrate the potential of the developed method for biomedical applications.


Influence of blood pulsation on diagnostic volume in pulse oximetry and photoplethysmography measurements.
Recent advances in the development of ultra-compact semiconductor lasers and technology of printed flexible hybrid electronics have opened broad perspectives for the design of new pulse oximetry and photoplethysmography devices. Conceptual design of optical diagnostic devices requires careful selection of various technical parameters, including spectral range; polarization and intensity of incident light; actual size, geometry, and sensitivity of the detector; and mutual position of the source and detector on the surface of skin. In the current study utilizing a unified Monte Carlo computational tool, we explore the variations in diagnostic volume due to arterial blood pulsation for typical transmitted and back-scattered probing configurations in a human finger. The results of computational studies show that the variations in diagnostic volumes due to arterial pulse wave are notably (up to 45%) different in visible and near-infrared spectral ranges in both transmitted and back-scattered probing geometries. While these variations are acceptable for relative measurements in pulse oximetry and/or photoplethysmography, for absolute measurements, an alignment normalization of diagnostic volume is required and can be done by a computational approach utilized in the framework of the current study.


Land use strategies to mitigate climate change in carbon dense temperate forests.
Strategies to mitigate carbon dioxide emissions through forestry activities have been proposed, but ecosystem process-based integration of climate change, enhanced CO2, disturbance from fire, and management actions at regional scales are extremely limited. Here, we examine the relative merits of afforestation, reforestation, management changes, and harvest residue bioenergy use in the Pacific Northwest. This region represents some of the highest carbon density forests in the world, which can store carbon in trees for 800 y or more. Oregon's net ecosystem carbon balance (NECB) was equivalent to 72% of total emissions in 2011-2015. By 2100, simulations show increased net carbon uptake with little change in wildfires. Reforestation, afforestation, lengthened harvest cycles on private lands, and restricting harvest on public lands increase NECB 56% by 2100, with the latter two actions contributing the most. Resultant cobenefits included water availability and biodiversity, primarily from increased forest area, age, and species diversity. Converting 127,000 ha of irrigated grass crops to native forests could decrease irrigation demand by 233 billion m3⋅y-1 Utilizing harvest residues for bioenergy production instead of leaving them in forests to decompose increased emissions in the short-term (50 y), reducing mitigation effectiveness. Increasing forest carbon on public lands reduced emissions compared with storage in wood products because the residence time is more than twice that of wood products. Hence, temperate forests with high carbon densities and lower vulnerability to mortality have substantial potential for reducing forest sector emissions. Our analysis framework provides a template for assessments in other temperate regions.


Epigenetics and bacterial infections.
Epigenetic mechanisms regulate expression of the genome to generate various cell types during development or orchestrate cellular responses to external stimuli. Recent studies highlight that bacteria can affect the chromatin structure and transcriptional program of host cells by influencing diverse epigenetic factors (i.e., histone modifications, DNA methylation, chromatin-associated complexes, noncoding RNAs, and RNA splicing factors). In this article, we first review the molecular bases of the epigenetic language and then describe the current state of research regarding how bacteria can alter epigenetic marks and machineries. Bacterial-induced epigenetic deregulations may affect host cell function either to promote host defense or to allow pathogen persistence. Thus, pathogenic bacteria can be considered as potential epimutagens able to reshape the epigenome. Their effects might generate specific, long-lasting imprints on host cells, leading to a memory of infection that influences immunity and might be at the origin of unexplained diseases.