Proteomic analysis distinguishes basaloid carcinoma as a distinct subtype of nonsmall cell lung carcinoma.
The histopathologic type of lung cancer is known to be correlated with tumor behavior and prognosis. However, this classification is subjective and no specific molecular markers have been identified. The aim of this study was to identify protein markers in different types of nonsmall cell lung cancers. Two-dimensional polyacrylamide gel electrophoresis analysis was performed with paired samples of three squamous cell carcinomas, three adenocarcinomas, four large cell carcinomas, and four basaloid carcinomas. We found that 25 proteins in 14 cases of lung cancer were differentially expressed compared to matched nontumorous lung tissues. Among these 25 proteins, 11 proteins were down-regulated and 14 were up-regulated in these four types of lung cancer. Alloalbumin venezia, selenium-binding protein 1, carbonic dehydratase, heat shock 20KD-like protein, and SM22 alpha protein were down-regulated in all 14 cases of lung cancer examined, whereas alpha enolase was consistently up-regulated. Supervised hierarchical cluster analysis based on the 25 differentially expressed proteins showed that basaloid carcinoma formed one independent group, whereas the other three cancer types were not uniquely classifiable. Our findings suggest that basaloid carcinoma is a unique subtype of nonsmall cell lung carcinoma.


Clinical and microbiological features of candiduria in critically ill adult patients in Shiraz, Iran (2016-2018): deviations from international guidelines and fluconazole therapeutic failure.
Candiduria is common among patients admitted to intensive care units (ICUs); however, clinical and microbiological data are limited, which accounts for non-compliance with international guidelines, including over treatment of asymptomatic candiduria that promotes antifungal resistance. This prospective study included adult patients admitted to ICUs of five referral hospitals in Shiraz, Iran, during 2016-2018. Species were identified by MALDI-TOF MS, and antifungal susceptibility was assessed according to CLSI M27-A3/S4. Among 2086 patients, 162 and 293 developed candiduria and bacteriuria, respectively. In total, 174 yeast isolates were collected; 88.5% were Candida albicans (91/174; 52.2%), C. glabrata (38/174; 21.8%), and C. tropicalis (25/174; 14.3%). Antifungal resistance was rare; only two isolates (one C. tropicalis and one C. krusei) were fluconazole resistant. Symptomatic candiduria was noted in 31.4% of patients (51/162); only 37% (19/51) of them were treated and 36.82% (7/19) showed fluconazole therapeutic failure. Two symptomatic patients developed candidemia shortly after candiduria. Among asymptomatic patients, 31.5% (35/111) were overtreated with fluconazole. The mortality rate was 25.3% (41/162); it did not differ between symptomatic and asymptomatic patients. Our results indicate that deviation from standard-of-care treatment for candiduria is a matter of concern given the high rate of fluconazole therapeutic failure among patients with symptomatic candiduria. Candiduria is an underestimated clinical presentation among critically ill patients and detailed data are scarce in this regard. Given the high rate of fluconazole therapeutic failure and development of candidemia in some cases, the mistreatment of candiduria should not be overlooked by clinicians.


[Coronary flow reserve and stenosis as the determinant of exercise capacity in patients with stable effort angina].
The coronary flow reserve was evaluated in 33 patients with stable effort angina and single vessel disease of the left anterior descending artery. We used a catheter-tip Doppler flow probe with injection of contrast media to the vessel in order to induce so-called reactive hyperemia. The reactive change was used as an index of the flow reserve of the coronary artery. In 15 patients out of 33, PTCA was performed and the change in the coronary flow reserve was evaluated. There was a good correlation between the coronary flow reserve and the exercise capacity in the treadmill ECG exercise test. As theoretically expected, the exercise capacity was determined by the coronary flow reserve. There was a poor correlation between the degree of stenosis shown in coronary arteriography and the coronary flow reserve. The degree of stenosis did not relate with the exercise capacity. The coronary flow reserve was increased with the procedure of PTCA. Though the patho-anatomic findings in coronary angiography give us important information to evaluate patients with ischemic heart disease, we concluded that these findings were still insufficient to allow us to estimate the flow reserve in the coronary artery. The exercise capacity did not relate well with the degree of stenosis.


Effects of testosterone and its metabolites on aromatase-immunoreactive cells in the quail brain: relationship with the activation of male reproductive behavior.
The enzyme aromatase converts testosterone (T) into 17 beta-estradiol and plays a pivotal role in the control of reproduction. In particular, the aromatase activity (AA) located in the preoptic area (POA) of male Japanese quail is a limiting step in the activation by T of copulatory behavior. Aromatase-immunoreactive (ARO-ir) cells of the POA are specifically localized within the cytoarchitectonic boundaries of the medial preoptic nucleus(POM), a sexually dimorphic and steroid-sensitive structure that is a necessary and sufficient site of steroid action in the activation of behavior. Stereotaxic implantation of aromatase inhibitors in but not around the POM strongly decreases the behavioral effects of a systemic treatment with T of castrated males. AA is decreased by castration and increased by aromatizable androgens and by estrogens. These changes have been independently documented at three levels of analysis: the enzymatic activity measured by radioenzymatic assays in vitro, the enzyme concentration evaluated semi-quantitatively by immunocytochemistry and the concentration of its messenger RNA quantified by reverse transcription-polymerase chain reaction (RT-PCR). These studies demonstrate that T acting mostly through its estrogenic metabolites regulates brain aromatase by acting essentially at the transcriptional level. Estrogens produced by central aromatization of T therefore have two independent roles: they activate male copulatory behavior and they regulate the synthesis of aromatase. Double label immunocytochemical studies demonstrate that estrogen receptors(ER) are found in all brain areas containing ARO-ir cells but the extent to which these markers are colocalized varies from one brain region to the other. More than 70% of ARO-ir cells contain detectable ER in the tuberal hypothalamus but less than 20% of the cells display this colocalization in the POA. This absence of ER in ARO-ir cells is also observed in the POA of the rat brain. This suggests that locally formed estrogens cannot control the behavior and the aromatase synthesis in an autocrine fashion in the cells where they were formed. Multi-neuronal networks need therefore to be considered. The behavioral activation could result from the action of estrogens in ER-positive cells located in the vicinity of the ARO-ir cells where they were produced (paracrine action). Alternatively, actions that do not involve the nuclear ER could be important. Immunocytochemical studies at the electron microscope level and biochemical assays of AA in purified synaptosomes indicate the presence of aromatase in presynaptic boutons. Estrogens formed at this level could directly affect the pre-and post-synaptic membrane or could directly modulate neurotransmission namely through their metabolization into catecholestrogens (CE) which are known to be powerful inhibitors of the catechol- omicron - methyl transferase (COMT). The inhibition of COMT should increase the catecholaminergic transmission. It is significant to note, in this respect, that high levels of 2-hydroxylase activity, the enzyme that catalyzes the transformation of estrogens in CE, are found in all brain areas that contain aromatase. On the other hand, the synthesis of aromatase should also be controlled by estrogens in an indirect, transynaptic manner very reminiscent of the way in which steroids indirectly control the production of LHRH. Fibers that are immunoreactive for tyrosine hydroxylase (synthesis of dopamine), dopamine beta-hydroxylase (synthesis of norepinephrine) or vasotocine have been identified in the close vicinity of ARO-ir cells in the POM and retrograde tracing has identified the origin of the dopaminergic and noradrenergic innervation of these areas. A few preliminary physiological experiments suggest that these catecholaminergic inputs regulate AA and presumably synthesis.


Progressive adaptation in regional parenchyma mechanics following extensive lung resection assessed by functional computed tomography.
In adult canines following major lung resection, the remaining lobes expand asymmetrically, associated with alveolar tissue regrowth, remodeling, and progressive functional compensation over many months. To permit noninvasive longitudinal assessment of regional growth and function, we performed serial high-resolution computed tomography (HRCT) on six male dogs (∼9 mo old, 25.0 ± 4.5 kg, ±SD) at 15 and 30 cmH(2)O transpulmonary pressure (Ptp) before resection (PRE) and 3 and 15 mo postresection (POST3 and POST15, respectively) of 65-70% of lung units. At POST3, lobar air volume increased 83-148% and tissue (including microvascular blood) volume 120-234% above PRE values without further changes at POST15. Lobar-specific compliance (Cs) increased 52-137% from PRE to POST3 and 28-79% from POST3 to POST15. Inflation-related parenchyma strain and shear were estimated by detailed registration of corresponding anatomical features at each Ptp. Within each lobe, regional displacement was most pronounced at the caudal region, whereas strain was pronounced in the periphery. Regional three-dimensional strain magnitudes increased heterogeneously from PRE to POST3, with further medial-lateral increases from POST3 to POST15. Lobar principal strains (PSs) were unchanged or modestly elevated postresection; changes in lobar maximum PS correlated inversely with changes in lobar air and tissue volumes. Lobar shear distortion increased in coronal and transverse planes at POST3 without further changes thereafter. These results establish a novel use of functional HRCT to map heterogeneous regional deformation during compensatory lung growth and illustrate a stimulus-response feedback loop whereby postresection mechanical stress initiates differential lobar regrowth and sustained remodeling, which in turn, relieves parenchyma stress and strain, resulting in progressive increases in lobar Cs and a delayed increase in whole lung Cs.


Translational learning from clinical studies predicts drug pharmacokinetics across patient populations.
Early indication of late-stage failure of novel candidate drugs could be facilitated by continuous integration, assessment, and transfer of knowledge acquired along pharmaceutical development programs. We here present a translational systems pharmacology workflow that combines drug cocktail probing in a specifically designed clinical study, physiologically based pharmacokinetic modeling, and Bayesian statistics to identify and transfer (patho-)physiological and drug-specific knowledge across distinct patient populations. Our work builds on two clinical investigations, one with 103 healthy volunteers and one with 79 diseased patients from which we systematically derived physiological information from pharmacokinetic data for a reference probe drug (midazolam) at the single-patient level. Taking into account the acquired knowledge describing (patho-)physiological alterations in the patient cohort allowed the successful prediction of the population pharmacokinetics of a second, candidate probe drug (torsemide) in the patient population. In addition, we identified significant relations of the acquired physiological processes to patient metadata from liver biopsies. The presented prototypical systems pharmacology approach is a proof of concept for model-based translation across different stages of pharmaceutical development programs. Applied consistently, it has the potential to systematically improve predictivity of pharmacokinetic simulations by incorporating the results of clinical trials and translating them to subsequent studies.


Predatory journals and conferences: why fake counts.
Predatory publishing poses a serious educational end ethical threat to the credibility of science. The aim of this review is to discuss the main features of this deceptive open-access model, its potential consequences and relevance for the whole scientific community. Recent reports showed that scholars and clinicians from all research fields, including anesthesiology, are facing an alarming invasion of predatory journals and, more recently, fake conferences. This review discusses key elements of these phenomena and proposes countermeasures to tackle the problem. Predatory journals and conferences are two sides of the same coin. As here reviewed, their deceptive practices have negative implications for scientists and clinicians, both educational and ethical. These range from publication of experimental data that are unreliable and poorly verified to inflated curricula and 'doped' academic careers. Because clinical practice is heavily based on research data, a solution is needed to ultimately ensure patients' safety.


Not taking responsibility: Equity trumps efficiency in allocation decisions.
When allocating resources, equity and efficiency may conflict. When resources are scarce and cannot be distributed equally, one may choose to destroy resources and reduce societal welfare to maintain equity among its members. We examined whether people are averse to inequitable outcomes per se or to being responsible for deciding how inequity should be implemented. Three scenario-based experiments and one incentivized experiment revealed that participants are inequity responsibility averse: when asked to decide which of the 2 equally deserving individuals should receive a reward, they rather discarded the reward than choosing who will get it. This tendency diminished significantly when participants had the possibility to use a random device to allocate the reward. The finding suggests that it is more difficult to be responsible for the way inequity is implemented than to create inequity per se. (PsycINFO Database Record


Elemental concentrations in the seed of mutants and natural variants of Arabidopsis thaliana grown under varying soil conditions.
The concentrations of mineral nutrients in seeds are critical to both the life cycle of plants as well as human nutrition. These concentrations are strongly influenced by soil conditions, as shown here by quantifying the concentration of 14 elements in seeds from Arabidopsis thaliana plants grown under four different soil conditions: standard, or modified with NaCl, heavy metals, or alkali. Each of the modified soils resulted in a unique change to the seed ionome (the mineral nutrient content of the seeds). To help identify the genetic networks regulating the seed ionome, changes in elemental concentrations were evaluated using mutants corresponding to 760 genes as well as 10 naturally occurring accessions. The frequency of ionomic phenotypes supports an estimate that as much as 11% of the A. thaliana genome encodes proteins of functional relevance to ion homeostasis in seeds. A subset of mutants were analyzed with two independent alleles, providing five examples of genes important for regulation of the seed ionome: SOS2, ABH1, CCC, At3g14280 and CNGC2. In a comparison of nine different accessions to a Col-0 reference, eight accessions were observed to have reproducible differences in elemental concentrations, seven of which were dependent on specific soil conditions. These results indicate that the A. thaliana seed ionome is distinct from the vegetative ionome, and that elemental analysis is a sensitive approach to identify genes controlling ion homeostasis, including those that regulate gene expression, phospho-regulation, and ion transport.


Topical therapies for oral lichen planus management and their efficacy: a narrative review.
Oral Lichen Planus (OLP) is a chronic inflammatory condition implicating T cell-mediated cytotoxicity, and involving oral mucosal surfaces. Several therapeutic regimens have been evaluated to treat OLP and pain related, but often without high level of evidence. Topical formulations are the favourite for the majority of cases; bioadhesive formulations have been considered very useful and practical for local drug delivery in oral mucosa, due to the increased residence time on the oral mucosa of the dosage forms and better therapeutic efficacy. In this narrative review, authors try to illustrate the current topical managements for OLP from the accessible literature on this topic. Steroids are very helpful in discomfort and making better quality of life: they are considered the first-line treatment even if they could cause secondary candidosis, and sometimes bad taste, nausea, dry mouth, sore throat or swollen mouth. Other substances or devices by topical administration are adopted especially when the first line approach is refractory. This is the case when retinol with its synthetic and natural analogues (retinoids), hyaluronic acid, or Aloe Vera are chosen. Recent topical applications for OLP therapy include phototherapy and low/high energy pulsing light; the treatment with extracorporeal photochemotherapy is also reasonable and promising. Finally, calcineurin inhibitors (i.e. cyclosporine, tacrolimus and pimecrolimus), antioxidant and biologics (i.e alefacept, efalizumab, basiliximab, TNF-α inhibitors - infliximab, rituximab) may be alternative approaches when OLP does not respond to the standard protocols. In this scenario, there are several studies on molecules different from glucocorticosteroids, but not sufficient or statistically adequate to justify their evidence-based use in OLP; large randomized placebo controlled trials are required to evaluate the safety and effectiveness of these non conventional therapies. In conclusion, since OLP is a chronic disease and requires long-term management, the dental/medical practitioner, who treats OLP patients, needs to know the natural history of OLP, how to monitor, and how to treat, taking in account all of the available modalities conventional and not, with pros and cons.


Patient and family attitudes regarding the practice of procedures on the newly deceased.
Performance of emergency lifesaving procedures is an integral part of emergency medicine resident training. To assess attitudes of ED patients regarding the practice of procedures on the newly deceased. A descriptive survey was administered to a convenience sample of ED patients and their families at two urban military Level-1 trauma centers. Subjects were asked about their overall opinions regarding the practice of nontherapeutic procedural skills on themselves or relatives immediately after death in the ED. Subgroup analysis included the issue of advanced permission and opinions regarding procedures defined by the investigators as noninvasive (e.g., laryngeal mask airway) or invasive (e.g., cricothyrotomy). Data were analyzed descriptively and with chi-square as appropriate. For comparison of proportions, a sample size of at least 140 was chosen for an alpha of 0.05 and a beta of 0.10 to detect an effect size of 0.3. Alpha was corrected for multiple comparisons prior to the study. Three hundred seventeen surveys were collected and 88% (n = 280) were complete. Seventy-five percent (n = 290) and 70% (n = 273) of the respondents agreed to after-death procedures on themselves or their relatives, respectively. However, only 40% (n = 106) and 50% (n = 131) would allow such procedures without prior permission. Seventy-one percent (n = 189) were willing to give permission in a living will, while 85% (n = 238) indicated support of a wallet card format. There was no significant difference in permission rates when contrasting individual noninvasive and invasive procedures. Most patients are willing to have procedures performed on themselves or relatives shortly after death, yet the majority request that permission be obtained in advance. A living will or carried card would be acceptable for such permission.


Ten-Year Trends in Direct Costs of COPD: A Population-Based Study.
Up-to-date estimates of burden of diseases are required for evidence-based decision-making. The objectives of this study were to determine the excess costs of COPD and its trend from 2001 to 2010 in British Columbia, Canada. We used British Columbia's administrative health data to construct a cohort of patients with COPD and a matched comparison cohort of subjects without COPD. We followed each patient from the time of first COPD-related health-care event (or equivalent time for the comparison cohort). Direct medical costs (in 2010 Canadian dollars [$]) were calculated based on billing records pertaining to hospital admissions, outpatient services use, medication dispensations, and community care services. We determined the excess medical costs of COPD by calculating the difference in overall medical costs between the COPD and the comparison cohorts. The COPD and comparison cohorts comprised 153,570 and 246,801 people, respectively (for both cohorts, mean age at entry was 66.9 years; 47.2% female patients). The excess costs of COPD during the study period were $5,452 per patient-year. Inpatient, outpatient, medication, and community care costs were responsible for 57%, 16%, 22%, and 5% of the excess costs, respectively. Excess costs increased by $296/person-y (P < .01), with hospital costs demonstrating the largest increase over time ($258/person-y; P < .01). The direct economic burden of COPD is high and has increased significantly between 2001 and 2010 over and above the increase in the health-care costs of the general population. Further investigation is required to elucidate the underlying reasons for the temporal increase in COPD direct costs.


Sequence analysis of porcine endogenous retrovirus long terminal repeats and identification of transcriptional regulatory regions.
Porcine cells express endogenous retroviruses, some of which are infectious for human cells. To better understand the replication of these porcine endogenous retroviruses (PERVs) in cells of different types and animal species, we have performed studies of the long terminal repeat (LTR) region of known gammaretroviral isolates of PERV. Nucleotide sequence determination of the LTRs of PERV-NIH, PERV-C, PERV-A, and PERV-B revealed that the PERV-A and PERV-B LTRs are identical, whereas the PERV-NIH and PERV-C LTRs have significant sequence differences in the U3 region between each other and with the LTRs of PERV-A and PERV-B. Sequence analysis revealed a similar organization of basal promoter elements compared with other gammaretroviruses, including the presence of enhancer-like repeat elements. The sequences of the PERV-NIH and PERV-C repeat element are similar to that of the PERV-A and PERV-B element with some differences in the organization of these repeats. The sequence of the PERV enhancer-like repeat elements differs significantly from those of other known gammaretroviral enhancers. The transcriptional activities of the PERV-A, PERV-B, and PERV-C LTRs relative to each other were similar in different cell types of different animal species as determined by transient expression assays. On the other hand, the PERV-NIH LTR was considerably weaker in these cell types. The transcriptional activity of all PERV LTRs was considerably lower in porcine ST-IOWA cells than in cell lines from other species. Deletion mutant analysis of the LTR of a PERV-NIH isolate identified regions that transactivate or repress transcription depending on the cell type.


SIRT1 gene polymorphisms affect the protein expression in cardiovascular diseases.
Cardiovascular disease (CVD), the leading cause of death worldwide, is related to gene-environment interactions due to epigenetic factors. SIRT1 protein and its downstream pathways are critical for both normal homeostasis and protection from CVD-induced defects. The aim of this study was to investigate the association between SIRT1 single nucleotide polymorphisms (SNPs) (rs7895833 A>G in the promoter region, rs7069102 C>G in intron 4 and rs2273773 C>T in exon 5 silent mutation) and SIRT1 and eNOS (endothelial nitric oxide synthase) protein expression as well as total antioxidant status (TAS), total oxidant status (TOS) and oxidative stress index (OSI) in CVD patients as compared to controls. The frequencies of mutant genotypes and alleles for rs7069102 and rs2273773 were significantly higher in patients with CVD compared to control group. The risk for CVD was increased by 2.4 times for rs7069102 and 1.9 times for rs2273773 in carriers of mutant allele compared with carriers of wild-type allele pointing the protective role of C allele for both SNPs against CVD. For rs7895833, there was no significant difference in genotype and allele distributions between groups. SIRT1 protein, TAS, TOS and OSI levels significantly increased in patients as compared to control group. In contrast, level of eNOS protein was considerably low in the CVD patients. An increase in the SIRT1 expression in the CVD patients carrying mutant genotype for rs7069102 and heterozygote genotype for all three SNPs was observed. This is the first study reporting an association between SIRT1 gene polymorphisms and the levels of SIRT1 and eNOS expressions as well as TAS, TOS and OSI.


Escherichia coli K1 RS218 interacts with human brain microvascular endothelial cells via type 1 fimbria bacteria in the fimbriated state.
Escherichia coli K1 is a major gram-negative organism causing neonatal meningitis. E. coli K1 binding to and invasion of human brain microvascular endothelial cells (HBMEC) are a prerequisite for E. coli penetration into the central nervous system in vivo. In the present study, we showed using DNA microarray analysis that E. coli K1 associated with HBMEC expressed significantly higher levels of the fim genes compared to nonassociated bacteria. We also showed that E. coli K1 binding to and invasion of HBMEC were significantly decreased with its fimH deletion mutant and type 1 fimbria locked-off mutant, while they were significantly increased with its type 1 fimbria locked-on mutant. E. coli K1 strains associated with HBMEC were predominantly type 1 fimbria phase-on (i.e., fimbriated) bacteria. Taken together, we showed for the first time that type 1 fimbriae play an important role in E. coli K1 binding to and invasion of HBMEC and that type 1 fimbria phase-on E. coli is the major population interacting with HBMEC.


A Systematic Review of Genetic Influence on Psychological Resilience.
When exposed to adversity, some individuals are at an increased risk of posttraumatic stress disorder, experiencing persistent biopsychosocial disturbances, whereas others adapt well, described as resilience. Resilience is a complex biopsychosocial phenomenon conceptualized as adaptation to adversity influenced by an individual's genetic variants, epistasis, epigenetics, and gene-by-environment interactions. Studies on psychological resilience have focused on behavioral and psychosocial variables with far less examination of the genetic contributions. The purpose of this review is to identify specific genetic variants contributing to the biological capacity for psychological resilience. PubMed and PsycINFO were searched using the following key words: psychological resilience AND genotype(s). Additional articles were identified from the Human Genome Epidemiology Navigator using the term resilience, psychological. Ten studies met the criteria. Six genes were empirically associated with psychological resilience: serotonin-transporter-linked polymorphic region ( 5-HTTLPR), dopamine receptor D4, brain-derived neurotrophic factor ( BDNF), corticotropin-releasing hormone receptor 1, oxytocin receptor and regulator of G-protein signaling 2 . The findings of this systematic review suggest that the L/L or L'/L' genotype of 5-HTTLPR and rs25531 in children/adolescents and the S/S or S'/S' genotype in adults are most frequently related to resilience. Additionally, the Val/Val genotype of rs6265 in BDNF in Caucasians was also associated with resilience. There are numerous factors contributing to the complexity of determining the genetic influence on resilience including analysis of rs25531, assumptions of the mode of inheritance, operationalization of resilience, demographic and population characteristics, sample size, and other types of genetic influence including epistasis and epigenetics. While current evidence is supportive, further investigation of the genetic influence on resilience is required.


Elder self-neglect: research and practice.
Elder self-neglect is a global public health and human rights issue that threatens older people's health and safety. It commonly refers to refusal or failure to provide oneself with care and protection in areas of food, water, clothing, hygiene, medication, living environments, and safety precautions. While prevalent, the status of self-neglecting individuals remains largely unclear, in particular within community-dwelling populations. By reviewing the epidemiology of elder self-neglect (definition, prevalence, risk factors, and consequences) to date, the present paper identifies key research gaps such as methodological inconsistency in case identification and measurement, and study designs that are inadequate to determine risk factors of self-neglect. More importantly, in light of the rapidly growing older population, relevant stakeholders (researchers, healthcare providers, social service providers, legal professionals, community organizations, and policymakers) must be prepared for an expected increasing number of self-neglect cases and enlarging scope of the problem. Hence, in this article, I present an overview regarding the management issues of elderly self-neglect related to the detection, assessment, reporting and referral, and decision-making capacity. Based on the current literature, the paper is aimed to explore the present knowledge and challenges, and how they can pave the way for solutions to self-neglect research, practice, and policy.


Retroviral insertional activation in a herpesvirus: transcriptional activation of US genes by an integrated long terminal repeat in a Marek's disease virus clone.
Insertional activation of host proto-oncogenes has been recognized as a basic mechanism by which nonacute retroviruses induce cancer. Our previous work has demonstrated that retroviruses can efficiently integrate into DNA virus genomes. Specifically, coinfection of cultured fibroblasts with a chicken herpesvirus, Marek's disease virus (MDV), and a chicken retrovirus results in frequent stable retroviral insertions into the herpesvirus genome. Such insertions could alter the expression of herpesvirus genes, possibly resulting in novel phenotypic properties. In this article, we report the characterization of a replication-competent clone of MDV with integrated retroviral sequences. This virus was isolated from a chicken following injection of fibroblasts coinfected with MDV and the retrovirus, reticuloendotheliosis virus. Transcripts originating from the reticuloendotheliosis virus long terminal repeat promoters were found to encode the adjoining MDV genes, SORF2, US1, and US10. This virus replicates well in culture but has an unusual phenotype in chickens, characterized by an attenuated virulence which produces no nerve lesions but, rather, severe thymic atrophy. While the causal relationship between the insertion and the observed phenotypes remains to be established, our data provide the first evidence of retroviral insertional activation of herpesvirus genes.


Evolution of radiotherapy techniques in breast conservation treatment.
Radiation therapy (RT) is an important component of breast cancer treatment that reduces local recurrence and improves survival after breast conservation. Breast conservation rates have increased significantly since the late 1980s and techniques have improved with greater awareness of the impact of radiation on the heart. An overview of randomized controlled trials of breast conservation using standard whole breast irradiation, whole breast hypofractionation, accelerated partial breast irradiation (APBI) and intraoperative radiation are reviewed. Selection criteria for breast conservation and the utility of adding a boost dose to the primary tumor site are reviewed. Modern dose constraints are documented and 10 different radiation techniques from the 1980s through to modern volumetric modulated arc therapy (VMAT) are compared for a patient where the breast and internal mammary nodes are treated. A radiation boost reduces the risk of a recurrence for most, but not all patients. Short courses of RT over 3-4 weeks are generally as effective as longer courses. Short-term follow-up of trials of APBI show promise for selected good prognosis subgroups. The role of intraoperative radiation remains controversial. In the last 30 years, there have been significant advances in radiation techniques. Modern radiotherapy equipment and techniques will reduce complications and improve survival rates.


Restaurant smoking restrictions and environmental tobacco smoke exposure.
This study evaluated the effectiveness of smoking restrictions. We measured particulate concentrations in restaurants with different levels of allowable smoking. Mean particulate concentrations were 70% higher in establishments without smoking restrictions compared with those with partial smoking restrictions. Concentrations in nonsmoking restaurants were reduced by an additional 20% to 30%. Measurements of cadmium, an environmental tobacco smoke (ETS) marker, implicated ETS as the major source of particulate in restaurants that allowed smoking. Partial smoking restrictions substantially reduce, but do not eliminate, ETS exposure in restaurants. Occupants of nonsmoking restaurants avoid ETS exposure but may experience substantial particulate exposures from cooking emissions.


Method to minimize the effects of polarizer leakage on reflectivity measurements.
The effects of polarizer leakage on reflectivity measurements have been determined analytically and experimentally. It is shown that for values of the extinction ratio larger than 10(-3) the inferred refractive index of dielectric materials from reflectivity measurements maybe in error by 27% or more. On the other hand, the real and imaginary parts of the index of carbonaceous materials may be in error by more than 30 and 60%, respectively. Furthermore, when the specularity index of smooth surfaces is to be determined, significant differences (68% or more) may result for the same range of values of the extinction ratio. A method is presented for correcting the reflectivity measurements for polarizer leakage based on the extinction ratio of the polarizer. In addition, analytical expressions are provided for the determination of the actual value of the extinction ratio of a given polarizing film at any wavelength. The effects of the typical and actual values of the extinction ratio on the inferred optical constants and specularity index of dielectric and absorbing materials are assessed.


Mediterranean Diet and Prevention of Chronic Diseases.
A large body of research data suggests that traditional dietary habits and lifestyle unique to the Mediterranean region (Mediterranean diet, MD) lower the incidence of chronic diseases and improve longevity. These data contrast with troubling statistics in the United States and other high income countries pointing to an increase in the incidence of chronic diseases and the projected explosion in cost of medical care associated with an aging population. In 2013, the MD was inscribed by UNESCO in the "Representative List of the Intangible Cultural Heritage of Humanity." The 2015-2020 Dietary Guidelines for Americans included the MD as a healthy dietary pattern. Therefore, specific objectives of this article are to provide an overview of the nutritional basis of this healthful diet, its metabolic benefits, and its role in multiple aspects of disease prevention and healthy aging. Whereas recommendations about the MD often focus on specific foods or bioactive compounds, we suggest that the eating pattern as a whole likely contributes to the health promoting effects of the MD.


Transplantation Versus Resection for Hilar Cholangiocarcinoma: An Argument for Shifting Treatment Paradigms for Resectable Disease.
To investigate the influence of type of surgery (transplant vs resection) on overall survival (OS) in patients with hilar cholangiocarcinoma (H-CCA). Outcomes after resection for H-CCA are poor, yet transplantation is currently only reserved for well-selected patients with unresectable disease. All patients with H-CCA who underwent resection from 2000 to 2015 at 10 institutions were included. Three institutions additionally had active H-CCA transplant protocols with similar selection criteria over similar time periods. Of 304 patients with suspected H-CCA, 234 underwent attempted resection and 70 were enrolled in a transplant protocol. Excluding incomplete/R2 resections (n = 43), patients who were enrolled, but did not undergo transplant (n = 24), and transplants without confirmed H-CCA diagnoses (n = 5), 191 patients underwent curative-intent resection and 41 curative-intent transplant. Compared with resection, transplant patients were younger (52 vs 65 years; P < 0.001), and more frequently had primary sclerosing cholangitis (PSC; 61% vs 2%; P < 0.001) and received chemotherapy and/or radiation (98% vs 57%; P < 0.001). Groups were otherwise similar in demographics and comorbidities. Patients who underwent transplant for confirmed H-CCA diagnosis had improved OS compared with resection (3-year: 72% vs 33%; 5-year: 64% vs 18%; P < 0.001). Among patients who underwent resection for tumors <3 cm with lymph-node negative disease, and excluding PSC patients, transplant was still associated with improved OS (3-year: 54% vs 44%; 5-year: 54% vs 29%; P = 0.03). Transplant remained associated with improved survival on intention-to-treat analysis, even after accounting for tumor size, lymph node status, and PSC (P = 0.049). Resection for hilar cholangiocarcinoma that meets criteria for transplantation (<3 cm, lymph-node negative disease) is associated with substantially decreased survival compared to transplant for the same criteria with unresectable disease. Prospective trials are needed and justified.


Salmonella enterica Typhimurium infection causes metabolic changes in chicken muscle involving AMPK, fatty acid and insulin/mTOR signaling.
Salmonella enterica serovar Typhimurium (Salmonella Typhimurium) infection of chickens that are more than a few days old results in asymptomatic cecal colonization with persistent shedding of bacteria. We hypothesized that while the bacterium colonizes and persists locally in the cecum it has systemic effects, including changes to metabolic pathways of skeletal muscle, influencing the physiology of the avian host. Using species-specific peptide arrays to perform kinome analysis on metabolic signaling pathways in skeletal muscle of Salmonella Typhimurium infected chickens, we have observed key metabolic changes that affected fatty acid and glucose metabolism through the 5'-adenosine monophosphate-activated protein kinase (AMPK) and the insulin/mammalian target of rapamycin (mTOR) signaling pathway. Over a three week time course of infection, we observed changes in the phosphorylation state of the AMPK protein, and proteins up and down the pathway. In addition, changes to a large subset of the protein intermediates of the insulin/mTOR pathway in the skeletal muscle were altered by infection. These changes occur in pathways with direct effects on fatty acid and glucose metabolism. This is the first report of significant cellular metabolic changes occurring systemically in chicken due to a Salmonella infection. These results have implications not only for animal production and health but also for the understanding of how Salmonella infection in the intestine can have widespread, systemic effects on the metabolism of chickens without disease-like symptoms.


Mice with a disrupted IFN-gamma gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE).
Experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, is an autoimmune disorder seen in mice and rats following immunization with myelin basic protein (MBP) or MBP-derived peptides. IFN-gamma, a cytokine produced by a variety of cells, is involved in many inflammatory and immune regulatory events. Contradictory results concerning exacerbations and the disease course were seen comparing injections of IFN-gamma in humans suffering from multiple sclerosis to studies using anti-IFN-gamma Abs in mice with EAE. To study the role of IFN-gamma and IFN-gamma-producing cells in EAE, we crossed IFN-gamma knockout mice (H-2b) (unable to produce IFN-gamma due to the disruption of the IFN-gamma gene) with an EAE-susceptible mouse strain, B10.PL (H-2u). EAE was seen in IFN-gamma knockout mice, heterozygotic (IFN-gamma +/-) mice, as well as wild-type littermates following immunization with MBP. Histologic analyses of the central nervous system of IFN-gamma knockout mice with EAE revealed massive infiltrates composed of lymphocytes, macrophages, and granulocytes. We conclude that the presence of IFN-gamma is not crucial to the induction or the clinical course of EAE.


Sitaxsentan for the treatment of pulmonary arterial hypertension: a 1-year, prospective, open-label observation of outcome and survival.
Despite advances in the management of pulmonary arterial hypertension (PAH), the mortality rate remains excessive. Long-term efficacy evaluations are needed to guide therapeutic management. The purpose of this study is to present 1-year observational data with two endothelin antagonists, sitaxsentan and bosentan, in a prospective, open-label study. The present study was a prospective, international, multicenter, randomized, open-label extension of the Sitaxsentan To Relieve Impaired Exercise-2 trial. All-cause mortality, time to discontinuation (all causes) from monotherapy, time to discontinuation due to adverse events, time to elevations in and time to discontinuation due to elevated hepatic transaminases, and time to first clinical worsening event were evaluated. Patients initially receiving sitaxsentan at 50 mg were excluded from the main analysis. The distributions of time-to-event variables are estimated using Kaplan-Meier methods, and treatment effects are evaluated using the Cox proportional hazards model. Patients treated with sitaxsentan at 100 mg had 96% overall survival and a 34% risk for a clinical worsening event by 1 year. In addition, there was a 6% risk of elevated aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) levels > 3 x upper limit of normal range (ULN) at 1 year and a 15% risk of discontinuation due to adverse events. Patients treated with bosentan had 88% overall survival and a 40% risk of a clinical worsening event by 1 year. In addition, there was a 14% risk for elevated AST and/or ALT levels > 3 x ULN at 1 year and a 30% risk of discontinuation due to adverse events. At 1 year, sitaxsentan therapy appears safe and efficacious for patients with PAH; reductions in mortality and the risk for clinical worsening events provide support for durability of efficacy.


Spatial reference in a bonobo gesture.
Great apes frequently produce gestures during social interactions to communicate in flexible, goal-directed ways [1-3], a feature with considerable relevance for the ongoing debate over the evolutionary origins of human language [1, 4]. But despite this shared feature with language, there has been a lack of evidence for semantic content in ape gestures. According to one authoritative view, ape gestures thus do not have any specific referential, iconic, or deictic content, a fundamental difference versus human gestures and spoken language [1, 5] that suggests these features have a more recent origin in human evolution, perhaps caused by a fundamental transition from ape-like individual intentionality to human-like shared intentionality [6]. Here, we revisit this human uniqueness claim with a study of a previously undescribed human-like beckoning gesture in bonobos that has potentially both deictic and iconic character. We analyzed beckoning in two groups of bonobos, kept under near natural environmental and social conditions at the Lola Ya Bonobo sanctuary near Kinshasa, Democratic Republic of Congo, in terms of its linguistic content and underlying communicative intention.


Biological effects of a disposable, canisterless negative pressure wound therapy system.
Recent developments of negative pressure wound therapy (NPWT) systems have focused on making pumps smaller, lighter, and more portable. The recently introduced PICO system manages wound fluid through a highly breathable film within the dressing, thereby negating the need for a canister, which allows greater mobility and patient concordance. The aim of this study is to compare the biological effects of this system compared to a traditional NPWT system. Laboratory tests were carried out to demonstrate the fluid handling properties of the PICO™ system. Porcine full thickness defect wounds and sutured incisional wounds were used to compare the biological effects. Wounds were treated with PICO dressings or traditional NPWT dressings and connected to either a PICO device or a traditional NPWT device. The PICO dressing manages exudate predominantly through evaporative loss (up to 85% of all fluid entering the dressing). Both traditional NPWT and the PICO system maintained therapeutic levels of negative pressure in all wounds. Both NPWT systems produced similar effects on wound edge contraction and microvascular blood flow in defect wounds. No significant changes in blood flow or wound contraction were noted in incision wounds for any NPWT combinations tested. The disposable, canisterless PICO NPWT system functions in the same manner as the traditional NPWT systems with regard to fluid handling, pressure transmission to the wound bed, tissue contraction, and changes in blood flow.


Nucleo-cytoplasmic relationships of oestrogen receptors in rat liver during the oestrous cycle and in response to administered natural and synthetic oestrogen.
Oestrogen receptors were measured in the cytosolic and purified nuclear fractions of rat liver. Both cytosolic and nuclear receptors bind oestrogen with high affinity (Kd = 1.47 and 2.28 nM respectively) and specificity similar to that of receptors in order oestrogen-target tissues such as the uterus. During the 4-day oestrous cycle the receptor content and distribution between cytosol and nucleus did not vary; in particular, the content of nuclear receptor did not appear to fluctuate in concert with known cyclic changes in the concentration of plasma oestrogen. Injection of 50 micrograms of oestradiol-17 beta or 10 micrograms of ethynyloestradiol resulted in a 4--6-fold increase in the nuclear receptor content, with a concomitant decrease in the unoccupied-receptor content of cytosol 1 h after injection. The nuclear receptors present after injection bind oestrogens with similar affinity (Kd = 2.78 nM) and specificity to receptors present in uninjected animals. The administration of lower doses of either oestrogen was less effective in producing increases in nuclear receptor content. Hence there is apparently substantial translocation of receptor to the nucleus in response to hyperphysiological doses of oestrogen, but not to the physiological changes in plasma oestrogen concentrations during the oestrous cycle. The response to exogenous oestrogens is discussed in relation to the clinical use of synthetic oestrogens and progestogens.


Electrolytes in bovine prepartum mammary secretions and their usefulness for predicting parturition.
Accurately predicting parturition in cows can be difficult because of the variability in gestation length and uncertainty of the time of parturition. The goal of the present study was to determine the electrolyte concentrations of prepartum mammary secretions of gravid cows and to investigate retrospectively the possible predictive relationships between these concentrations and the time of parturition. Twenty-three cows were sampled once daily for 3 to 12 d before they calved. The concentrations of calcium, inorganic phosphorus, chloride, magnesium, sodium, and potassium were determined by photometric methods. In addition, the concentrations of calcium, magnesium, and inorganic phosphorus were determined using rapid test kits. The correlation between the photometrically measured electrolyte concentrations and the time of parturition was highest for inorganic phosphorus (r = 0.74). The inorganic phosphorus concentration was 11.8 to 26.5 mmol/L in cows that calved within 24 h of sample collection. When 11.8 mmol/L was used as a cutoff concentration for inorganic phosphorus, 21.7, 47.8, and 87.0% of cows calved within 24, 48, and 72 h, respectively. Within 12 d prepartum, the time of parturition can be estimated, with an error of +/- 32.4 h, by using the results of simultaneous determination of inorganic phosphorus and sodium concentrations in mammary secretions and a formula derived from a multiple regression analysis. The results of a phosphate field test positively and significantly correlated with those of the photometric analysis (r = 0.69) and the time of parturition (r = 0.41).


Upregulation of osteopontin expression in renal cortex of streptozotocin-induced diabetic rats is mediated by bradykinin.
The model of streptozotocin (STZ)-induced diabetes in Wistar rats was used to study the expression of osteopontin during development of diabetic nephropathy. Diabetes was confirmed by serum glucose levels exceeding 16 mmol/l during the experimental period of 12 weeks. During this period of time, diabetic nephropathy developed, as characterized by a reduced glomerular filtration rate (2.7 +/- 0.3 ml/min in controls vs. 1.7 +/- 0.1 ml/min in diabetic rats) and proteinuria (8.3 +/- 1.7 mg/24 h in controls vs. 22.0 +/- 4 mg/24 h in diabetic rats). Northern blot analysis revealed a time-dependent upregulation of renal cortical osteopontin expression reaching 138 +/- 6% of control levels after 2 weeks and 290 +/- 30% (mean +/- SE, n = 6-9) after 12 weeks. By immunostaining, the increased osteopontin expression could be located to the tubular epithelium of the renal cortex. Chronic treatment of animals with ramipril (3 mg/kg) during the 12-week experimental period led to a further increase in osteopontin mRNA expression in diabetic animals, amounting to 570 +/- 73% (mean +/- SE, n = 6) of controls. Increased levels of osteopontin were not associated with accumulation of monocyte/macrophages that were identified by the cell type specific monoclonal antibody ED-1. The increased osteopontin expression in ramipril-pretreated rats was abolished by application of the bradykinin B2-receptor antagonist, icatibant (0.5 mg/kg). In addition, increased osteopontin expression in diabetic rats, which did not receive any treatment after STZ injection, could as well be reduced by icatibant given for the final 2 weeks of the experimental period. These data suggest that a strong bradykinin B2-receptor-mediated upregulation of osteopontin occurs during the pathogenesis of experimental diabetic nephropathy in rats.


Bacteriological profile of community acquired acute bacterial meningitis: a ten-year retrospective study in a tertiary neurocare centre in South India.
Ten years retrospective study to evaluate the bacteriological spectrum of community acquired acute bacterial meningitis (CAABM). Cerebrospinal fluid (CSF) samples from 385 clinically suspected cases of pyogenic meningitis were processed for cell counts, cytospin Gram stain, culture, antigen detection by latex agglutination (LAT) and antibiotic susceptibility test. Eighteen of these CSF samples were also subjected to a polymerase chain reaction (PCR) assay for detection of pneumococcal DNA. The etiological agent could be identified in 284 (73.8%) of the total 385 cases by culture and/or smear and /or LAT. Streptococcus pneumoniae was the predominant pathogen accounting for 238 (61.8%) cases. Haemophilus influenzae and Neisseria meningitidis accounted for 7 (1.8%) and 4 (1%) cases respectively. Other gram negative bacilli, Streptococcus spp. and Staphylococcus aureus were isolated from 19 (4.9%), 9 (2.3%) and 7 (1.8%) cases respectively. Streptococcus pneumoniae remains the major aetiological agent of CAABM both in adults and children in our set-up. No penicillin resistance was detected among the isolates. Further research should focus on preventable aspects of CAABM, especially pneumococcal vaccines, to help reduce the disease burden.


Off-the-shelf human decellularized tissue-engineered heart valves in a non-human primate model.
Heart valve tissue engineering based on decellularized xenogenic or allogenic starter matrices has shown promising first clinical results. However, the availability of healthy homologous donor valves is limited and xenogenic materials are associated with infectious and immunologic risks. To address such limitations, biodegradable synthetic materials have been successfully used for the creation of living autologous tissue-engineered heart valves (TEHVs) in vitro. Since these classical tissue engineering technologies necessitate substantial infrastructure and logistics, we recently introduced decellularized TEHVs (dTEHVs), based on biodegradable synthetic materials and vascular-derived cells, and successfully created a potential off-the-shelf starter matrix for guided tissue regeneration. Here, we investigate the host repopulation capacity of such dTEHVs in a non-human primate model with up to 8 weeks follow-up. After minimally invasive delivery into the orthotopic pulmonary position, dTEHVs revealed mobile and thin leaflets after 8 weeks of follow-up. Furthermore, mild-moderate valvular insufficiency and relative leaflet shortening were detected. However, in comparison to the decellularized human native heart valve control - representing currently used homografts - dTEHVs showed remarkable rapid cellular repopulation. Given this substantial in situ remodeling capacity, these results suggest that human cell-derived bioengineered decellularized materials represent a promising and clinically relevant starter matrix for heart valve tissue engineering. These biomaterials may ultimately overcome the limitations of currently used valve replacements by providing homologous, non-immunogenic, off-the-shelf replacement constructs.


Sagittal plane ground reaction forces, centre of pressure and centre of mass in trotting horses.
The aims of this study were to measure ground reaction forces (GRFs) of concurrently loaded limbs and to evaluate spatial relationships between the centre of pressure (COP) and centre of mass (COM) in trotting horses. Kinematic (120Hz) and GRF data were collected at trot from three trials of eight horses using four force plates (960 Hz). Forelimb and hind limb GRFs were measured, COP was calculated from the resultant vertical GRF vector and COM was calculated by summation of weighted segmental COMs. Peak total vertical force (19.3 ± 1.3N/kg at 45.1 ± 2.3% diagonal stance) coincided with zero total longitudinal force (45.1 ± 2.4% stance). Initially, COP position corresponded with the fore or hind hoof of the diagonal that contacted the ground earlier. During diagonal overlap, COP position reflected forelimb contribution to total vertical GRF; it maintained a fairly constant position relative to the base of support through the middle part of stance, then moved cranially in the last third of stance towards the fore hoof, which was always the last hoof to leave the ground. The COM moved forward continuously; its longitudinal velocity decreased with the net braking force in early stance and increased with the net propulsive force in late stance. The COM was caudal to the COP in early stance, coincident at 35.8 ± 4.4% stance and was maximally ahead of the COP at 67.6 ± 4.8% stance. Changes in the spatial relationship between COP and COM affect the moment arms of the forelimb and hind limb vertical GRFs and their effect in generating a pitching torque around the COM.


Crystal structures of ternary complexes of archaeal B-family DNA polymerases.
Archaeal B-family polymerases drive biotechnology by accepting a wide substrate range of chemically modified nucleotides. By now no structural data for archaeal B-family DNA polymerases in a closed, ternary complex are available, which would be the basis for developing next generation nucleotides. We present the ternary crystal structures of KOD and 9°N DNA polymerases complexed with DNA and the incoming dATP. The structures reveal a third metal ion in the active site, which was so far only observed for the eukaryotic B-family DNA polymerase δ and no other B-family DNA polymerase. The structures reveal a wide inner channel and numerous interactions with the template strand that provide space for modifications within the enzyme and may account for the high processivity, respectively. The crystal structures provide insights into the superiority over other DNA polymerases concerning the acceptance of modified nucleotides.


Variations in the human pain stress experience mediated by ventral and dorsal basal ganglia dopamine activity.
In addition to its involvement in motor control and in encoding reward value, increasing evidence also implicates basal ganglia dopaminergic mechanisms in responses to stress and aversive stimuli. Basal ganglia dopamine (DA) neurotransmission may then respond to environmental events depending on their saliency, orienting the subsequent responses of the organism to both positive and negative stimuli. Here we examined the involvement of DA neurotransmission in the human response to pain, a robust physical and emotional stressor across species. Positron emission tomography with the DA D2 receptor antagonist radiotracer [11C]raclopride detected significant activation of DA release in dorsal and ventral regions of the basal ganglia of healthy volunteers. Activation of nigrostriatal (dorsal nucleus caudate and putamen) DA D2 receptor-mediated neurotransmission was positively associated with individual variations in subjective ratings of sensory and affective qualities of the pain. In contrast, mesolimbic (nucleus accumbens) DA activation, which may impact on both D2 and D3 receptors, was exclusively associated with variations in the emotional responses of the individual during the pain challenge (increases in negative affect and fear ratings). These data demonstrate that basal ganglia dopamine D2 receptor-mediated neurotransmission is involved in responses to pain and that it contributes to individual variations in the pain experience at the levels of physical and emotional elements, albeit with different neuroanatomical substrates.


'There's more to a person than what's in front of you': Nursing students' experiences of consumer taught mental health education.
Holistic and person-centred nursing care is commonly regarded as fundamental to nursing practice. These approaches are complementary to recovery which is rapidly becoming the preferred mode of practice within mental health. The willingness and ability of nurses to adopt recovery-oriented practice is essential to services realizing recovery goals. Involving consumers (referred herein as Experts by Experience) in mental health nursing education has demonstrated positive impact on the skills and attitudes of nursing students. A qualitative exploratory research project was undertaken to examine the perspectives of undergraduate nursing students to Expert by Experience-led teaching as part of a co-produced learning module developed through an international study. Focus groups were held with students at each site. Data were analysed thematically. Understanding the person behind the diagnosis was a major theme, including subthemes: person-centred care/seeing the whole person; getting to know the person, understanding, listening; and challenging the medical model, embracing recovery. Participants described recognizing consumers as far more than their psychiatric diagnoses, and the importance of person-centred care and recovery-oriented practice. Understanding the individuality of consumers, their needs and goals, is crucial in mental health and all areas of nursing practice. These findings suggest that recovery, taught by Experts by Experience, is effective and impactful on students' approach to practice. Further research addressing the impact of Experts by Experience is crucial to enhance our understanding of ways to facilitate the development of recovery-oriented practice in mental health and holistic and person-centred practice in all areas of health care.


The epoxy group of pramanicin is required for the optimal endothelium-dependent relaxation of rat aorta.
The vascular effects of a newly discovered anti-fungal agent, pramanicin (PMC), and its two analogues, PMC-A, in which the epoxy group is replaced by a - HC = CH - bond, and PMC-B, on which the diene is converted to the saturated (CH(2))(4)-derivative, respectively, were investigated in rat aorta. All three compounds caused an initial endothelial-dependent relaxation, which is prevented either by removal of endothelium or inclusion of the nitric oxide synthase inhibitor L-NAME. Upon prolonged incubation with the aortic rings, they also caused endothelial cell dysfunction characterized as reduced relaxation to carbachol (CCh). These effects were the strongest for PMC, being completely inhibitory at 20 microM after 30 min incubation, whereas those of PMC-A and PMC-B were smaller and comparable with each other, causing 30 - 40% inhibition at 20 micro M. PMC and its analogues had no effect on KCl-induced contraction and also had no effect on relaxation induced by sodium nitroprusside, suggesting that these compounds had no effect on the basic mechanisms of the contractile elements. Phenylephrine (PE)-induced contraction, however, was significantly reduced in the presence of these compounds, the inhibitory effect being strongest with PMC, but this inhibitory action was rapidly reversible and not of the competitive mode with respect to PE. We conclude that the epoxy group in PMC is required for the optimal vascular effects. We have discussed and speculated upon the possible mechanisms of action of PMC. The potent, selective, and irreversible inhibitory effect of PMC on the endothelial function points to its potential development into an anti-angiogenic drug.


Metagenomic analysis of two enhanced biological phosphorus removal (EBPR) sludge communities.
Enhanced biological phosphorus removal (EBPR) is one of the best-studied microbially mediated industrial processes because of its ecological and economic relevance. Despite this, it is not well understood at the metabolic level. Here we present a metagenomic analysis of two lab-scale EBPR sludges dominated by the uncultured bacterium, "Candidatus Accumulibacter phosphatis." The analysis sheds light on several controversies in EBPR metabolic models and provides hypotheses explaining the dominance of A. phosphatis in this habitat, its lifestyle outside EBPR and probable cultivation requirements. Comparison of the same species from different EBPR sludges highlights recent evolutionary dynamics in the A. phosphatis genome that could be linked to mechanisms for environmental adaptation. In spite of an apparent lack of phylogenetic overlap in the flanking communities of the two sludges studied, common functional themes were found, at least one of them complementary to the inferred metabolism of the dominant organism. The present study provides a much needed blueprint for a systems-level understanding of EBPR and illustrates that metagenomics enables detailed, often novel, insights into even well-studied biological systems.


Enhancement of growth of virulent strains of Escherichia coli by interleukin-1.
Interleukin-1 (IL-1) is a polypeptide cytokine that mediates many physiological responses to infection and inflammation and is a growth factor for certain mammalian cells. Virulent and avirulent clinical isolates of Escherichia coli were grown in culture media in the presence of human IL-1. IL-1 beta, but not tumor necrosis factor or IL-4, enhanced the growth of virulent, but not avirulent, E. coli. This enhancement was blocked by the IL-1 receptor antagonist (IL-1ra). Radiolabeled IL-1 bound to virulent but not avirulent E. coli in a specific and saturable fashion; IL-1ra inhibited this binding. Thus, human IL-1 may recognize a functional IL-1-like receptor structure on virulent E. coli and may be a virulence factor for bacterial pathogenicity.


Microbiology of Bloodstream Infections in Children After Hematopoietic Stem Cell Transplantation: A Single-Center Experience Over Two Decades (1997-2017).
Bloodstream infections (BSIs) occur frequently after hematopoietic stem cell transplantation (HSCT). We examined the microbiology of BSI in pediatric HSCT recipients over a 2-decade period at our institution to inform empirical antimicrobial prescribing and infection prevention strategies. We conducted a retrospective cohort study of children (<18 years) who underwent HSCT at Duke University between 1997 and 2015. We used recurrent-event gap-time Cox proportional hazards models to determine the hazards of all-cause and cause-specific BSI according to HSCT year. We compared the median time to BSI by causative organism type and evaluated for temporal trends in the prevalence of antibiotic resistance among causative organisms. A total of 865 BSI occurred in 1311 children, including 412 (48%) Gram-positive bacterial, 196 (23%) Gram-negative bacterial, 56 (6%) fungal, 23 (3%) mycobacterial, and 178 (21%) polymicrobial BSI. The hazard of all BSIs did not change substantially over time during the study period, but the hazard of fungal BSIs declined over time during the study period (P = .04). Most fungal BSIs (82%) occurred in the first 100 days after HSCT, whereas mycobacterial BSIs occurred later after HSCT than BSIs caused by other organisms (P < .0001). The prevalence of vancomycin resistance among BSIs caused by Enterococcus faecium increased during the study period (P = .0007). The risk of 2-year mortality in children was increased with BSI (P = .02), Gram-negative bacterial BSI (P = .02), and fungal BSI (P < .0001). Despite expanded practices for BSI prevention over the past several decades, the incidence of BSI remains high in pediatric HSCT recipients at our institution. Additional strategies are urgently needed to effectively prevent BSIs in this high-risk population.


The B73 maize genome: complexity, diversity, and dynamics.
We report an improved draft nucleotide sequence of the 2.3-gigabase genome of maize, an important crop plant and model for biological research. Over 32,000 genes were predicted, of which 99.8% were placed on reference chromosomes. Nearly 85% of the genome is composed of hundreds of families of transposable elements, dispersed nonuniformly across the genome. These were responsible for the capture and amplification of numerous gene fragments and affect the composition, sizes, and positions of centromeres. We also report on the correlation of methylation-poor regions with Mu transposon insertions and recombination, and copy number variants with insertions and/or deletions, as well as how uneven gene losses between duplicated regions were involved in returning an ancient allotetraploid to a genetically diploid state. These analyses inform and set the stage for further investigations to improve our understanding of the domestication and agricultural improvements of maize.


Regulating Black-Box Medicine.
Data drive modern medicine. And our tools to analyze those data are growing ever more powerful. As health data are collected in greater and greater amounts, sophisticated algorithms based on those data can drive medical innovation, improve the process of care, and increase efficiency. Those algorithms, however, vary widely in quality. Some are accurate and powerful, while others may be riddled with errors or based on faulty science. When an opaque algorithm recommends an insulin dose to a diabetic patient, how do we know that dose is correct? Patients, providers, and insurers face substantial difficulties in identifying high-quality algorithms; they lack both expertise and proprietary information. How should we ensure that medical algorithms are safe and effective? Medical algorithms need regulatory oversight, but that oversight must be appropriately tailored. Unfortunately, the Food and Drug Administration (FDA) has suggested that it will regulate algorithms under its traditional framework, a relatively rigid system that is likely to stifle innovation and to block the development of more flexible, current algorithms. This Article draws upon ideas from the new governance movement to suggest a different path. FDA should pursue a more adaptive regulatory approach with requirements that developers disclose information underlying their algorithms. Disclosure would allow FDA oversight to be supplemented with evaluation by providers, hospitals, and insurers. This collaborative approach would supplement the agency's review with ongoing real-world feedback from sophisticated market actors. Medical algorithms have tremendous potential, but ensuring that such potential is developed in high-quality ways demands a careful balancing between public and private oversight, and a role for FDA that mediates--but does not dominate--the rapidly developing industry.


Coagulation-flocculation for lignin removal from wastewater - a review.
Industrial discharge has tremendously increased inorganic pollutants in water bodies all over the world. Paper and pulp effluent is included in one of the most pollution generating discharges containing complex chemical compounds such as lignin. For clean and healthy water resources, the recovery of lignin from wastewater from the paper and pulp industry is of high importance. Available chemical and biological technologies for removal of lignin have certain drawbacks. Coagulation and flocculation is not only the economic but also the effective method for removal of lignin. The present review highlights available coagulants employed for removal of lignin from paper and pulp wastewater. Each coagulant is pH dependent and shows varied results with change in effluent characteristics. The hydrolysis products of aluminium-based coagulants, iron-based coagulants and copper sulphate have positive charges. These positive charges promote formation of flocs through charged neutralisation or sweep flocculation. In the case of titanium-based coagulants, hydrolysis product is negatively charged and mode is heterocoagulation. Ninety percent recovery of lignin is achieved by using a mixture of oxotitanium sulphate and aluminium sulphate and 80% with aluminium sulphate. Virtually complete recovery of lignin is observed with oxotitanium sulphate.


AHRQ series paper 5: grading the strength of a body of evidence when comparing medical interventions--agency for healthcare research and quality and the effective health-care program.
To establish guidance on grading strength of evidence for the Evidence-based Practice Center (EPC) program of the U.S. Agency for Healthcare Research and Quality. Authors reviewed authoritative systems for grading strength of evidence, identified domains and methods that should be considered when grading bodies of evidence in systematic reviews, considered public comments on an earlier draft, and discussed the approach with representatives of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) working group. The EPC approach is conceptually similar to the GRADE system of evidence rating; it requires assessment of four domains: risk of bias, consistency, directness, and precision. Additional domains to be used when appropriate include dose-response association, presence of confounders that would diminish an observed effect, strength of association, and publication bias. Strength of evidence receives a single grade: high, moderate, low, or insufficient. We give definitions, examples, mechanisms for scoring domains, and an approach for assigning strength of evidence. EPCs should grade strength of evidence separately for each major outcome and, for comparative effectiveness reviews, all major comparisons. We will collaborate with the GRADE group to address ongoing challenges in assessing the strength of evidence.


Inter-relationships of the chronobiotic, melatonin, with leptin and adiponectin: implications for obesity.
Obesity and its medical complications represent a significant problem throughout the world. In recent decades, mechanisms underlying the progression of obesity have been intensively examined. The involvement of both the behavioral aspects, such as calorie-rich diet, low physical activity and sleep deprivation, and the intrinsic factors, including adipose tissue deregulation, chronic inflammation, oxidative stress, and chronodisruption, has been identified. The circadian disturbances of the adipose tissue endocrine function have been correlated with obesity. Leptin and adiponectin are adipokines strongly associated with glucose and lipid metabolism and with energy balance. Their synthesis and secretion display circadian rhythms that are disturbed in the obese state. Hyperleptinemia resulting in leptin resistance, and hypo-adiponectinemia have been linked to the pathophysiology of the obesity-related disorders. A deficiency of melatonin, one of the consequences of sleep deprivation, has also been demonstrated to correlate with obesity. Melatonin is a pineal secretory product involved in numerous actions, such as regulation of internal biological clocks and energy metabolism, and it functions as an antioxidant and as an anti-inflammatory agent. There exists a substantial amount of evidence supporting the beneficial effects of melatonin supplementation on obesity and its complications. In the current review, the results of studies related to the interactions between melatonin, and both leptin and adiponectin are discussed. Despite the existence of some inconsistencies, melatonin has been found to normalize the expression and secretion patterns of both adipokines. These results support the concept of melatonin as a potential therapeutic agent for obesity and related disorders.


Implications of access, utilization and need for oral health care by the non-institutionalized and institutionalized elderly on the dental delivery system.
Oral health is integral to an older adult's general health and quality of life, and basic oral health services are an essential component of primary health care. The elderly should receive special consideration in terms of their oral health care needs since they: 1) may have unique problems accessing the health care delivery system; 2) experience different patterns and prevalence rates of oral diseases; and 3) may have characteristics that affect the amount and types of dental treatment and the method by which it is performed. Older adults are maintaining their natural teeth into their later years, and epidemiologic trends suggest the increasing need for dental services by older adults. Yet dental utilization rates are lower for older adults than for younger age groups, and barriers to care include the cost of dental care, the lack of perceived need for care, transportation problems, and fear. Oral diseases and impairments are most commonly experienced by those segments of society least able to obtain dental care. Economically and socially disadvantaged older adults and the physically impaired are more likely to experience tooth loss and edentulism, untreated dental decay and periodontal diseases. Adults over the age of 65 years have the lowest proportion of dental expenses reimbursed by private dental insurance (10 percent), and the highest percentage of out-of-pocket dental expenses (79 percent), as compared to all other age groups. Of the two largest public programs, Medicare does not pay for most dental services, and Medicaid (Title XIX), does not offer dental benefits for adults in most states. Although the majority of older adults live independently in the community, there is a growing number of elders with special needs that require long term care either at home or in an institution. These frail and functionally dependent elders have significant dental needs, and experience greater barriers to receiving dental care as compared to the independent elderly. Additional research is needed to accurately characterize the oral health status and needs of the growing number of homebound and institutionalized elders. This will be of growing importance with the emergence of the vast array of home health care services available to older adults, and the changing emphasis on home care often seen as the preferred and lower cost alternative to nursing home care.


Worldwide incidence of primary nervous system neoplasms. Geographical, racial and sex differences, 1960-1977.
International and interregional comparisons of average annual age-adjusted incidence rates for primary tumours of the nervous system showed marked variations. The highest rates were observed in those areas having high socioeconomic levels. In communities with multiple racial groups the highest rates were in Caucasians. Migrant populations retained rates close to those found in the country of origin. The majority of populations showed modest increases only while about one-third showed a decrease in the incidence rates during a period of approximately 15 years. Overall, there was a male excess. It is suggested that differences in medical practices (including availability of specialist expertise), diagnostic facilities and individual registry practices account for some of the variations observed. However, the possible aetiological roles of genetic, racial, hormonal and environmental factors need to be evaluated to explain the consistently higher incidence rates in Caucasians and in males of all races.


Factors associated with first sexual intercourse among mothers with 14-16 years of age from Porto Alegre/RS, Brazil.
This study analyzed the factors associated with first sexual intercourse among 427 mothers with 14-16 years of age from Porto Alegre (RS), Brazil. Data on adolescent socio-demographic status (skin color, religion and schooling gap) and reproductive aspects (age at menarche, age at first sexual intercourse, partnership in first sexual intercourse and partner's age) were collected through household survey. Data analysis was performed using bivariate and multivariate analysis through Poisson regression with robust variance. Among adolescents with early first sexual intercourse (up to 14 years), 77.4% had menarche at up to 12 years of age and 16.4% had casual partners in the first sexual intercourse. These variables were associated with the outcome and showed that early menarche (OR=1.26; CI 95%:1.04-1.52) and casual partner at first sexual intercourse (OR=1.28; CI 95%:1.09-1.49) increase by respectively 26% and 28% the prevalence of early first sexual intercourse. This study highlights the need to strengthen health programs and policies already implemented, such as the School Health Program, as well as reinforces that parents and teachers need to be oriented in an integrated manner in order to facilitate dialogue with adolescents and provide adequate counseling.


Fully automated tissue segmentation of the prescription isodose region delineated through the Gamma knife plan for cerebral arteriovenous malformation (AVM) using fuzzy C-means (FCM) clustering.
Gamma knife radiosurgery (GKRS) is a common treatment for cerebral arterio-venous malformations (AVMs), particularly in cases where the malformation is deep-seated, large, or in eloquent areas of the brain. Unfortunately, these procedures can result in radiation injury to brain parenchyma. The fact that every AVM is unique in its vascular morphology makes it nearly impossible to exclude brain parenchyma from isodose radiation exposure during the formulation of a GKRS plan. Calculating the percentages of the various forms of tissue exposed to specific doses of radiation is crucial to understanding the clinical responses and causes of brain parenchyma injury following GKRS for AVM. In this study, we developed a fully automated algorithm using unsupervised classification via fuzzy c-means clustering for the analysis of T2 weighted images used in a Gamma knife plan. This algorithm is able to calculate the percentages of nidus, brain tissue, and cerebrospinal fluid (CSF) within the prescription isodose radiation exposure region. The proposed algorithm was used to assess the treatment plan of 25 patients with AVM who had undergone GKRS. The Dice similarity index (SI) was used to determine the degree of agreement between the results obtained using the algorithm and a visually guided manual method (the gold standard) performed by an experienced neurosurgeon. In the nidus, the SI was (74.86 ± 1.30%) (mean ± standard deviation), the sensitivity was (83.05 ± 11.91)%, and the specificity was (86.73 ± 10.31)%. In brain tissue, the SI was (79.50 ± 6.01)%, the sensitivity was (73.05 ± 9.77)%, and the specificity was (85.53 ± 7.13)%. In the CSF, the SI was (69.57 ± 15.26)%, the sensitivity was (89.86 ± 5.87)%, and the specificity was (92.36 ± 4.35)%. The proposed clustering algorithm provides precise percentages of the various types of tissue within the prescription isodose region in the T2 weighted images used in the GKRS plan for AVM. Our results shed light on the causes of brain radiation injury after GKRS for AVM. In the future, this system could be used to improve outcomes and avoid complications associated with GKRS treatment.


Mouse placental macrophages have a decreased ability to present antigen.
Large numbers of macrophages can be found in an animal's uteroplacental unit. This high concentration of macrophages suggests they must play an important role during placental development. To gain a better understanding of the functional capacity of placental macrophages, we have obtained a highly enriched placental macrophage culture and have derived several cell lines from this population. Both placental macrophages and cell lines show colony-stimulating factor 1-dependent growth, express Fc receptors, and can perform Fc-receptor-mediated phagocytosis. In addition, they express macrophage markers Mac-1, F4/80, and CD14. Although placental macrophages express major histocompatibility complex class II molecules constitutively, they display a decreased ability to present protein antigens to T cells. Since primary fetal liver macrophages of the same gestational stage also show a decreased ability to present antigens, this phenomenon may reflect a developmental stage of macrophages.


Bovine leukemia virus p24 antibodies reflect blood proviral load.
Bovine leukemia virus (BLV) is worldwide distributed and highly endemic in Argentina. Among the strategies to prevent BLV dissemination, a control plan based on the selective segregation of animals according to their proviral load (PVL) is promising for our dairy productive system. The objective of this work was to study the relationship between the blood PVL and the antibody level, in order to identify whether the individual humoral response, i.e. the anti-p24 or anti-whole-BLV particle, could be used as a marker of the blood level of infection and thus help to recruit animals that may pose a lower risk of dissemination under natural conditions. The prevalence of p24 antibodies on the 15 farms studied was over 66%. The prevalence of p24 and whole-BLV antibodies and PVL quantification were analyzed in all the samples (n = 196) taken from herds T1 and 51. ROC analysis showed a higher AUC for p24 antibodies than whole-BLV antibodies (Z(reactivity): 3.55, P < 0.001; Z(titer): 2.88, P < 0.01), and as consequence a better performance to predict the proviral load status in herd 51. No significant differences were found between the performance of p24 and whole-BLV antibodies in herd T1. A significant positive correlation was observed between PVL values and p24 antibody reactivity in both farms (r (T1) = 0.7, P < 0.001, r (51) = 0.71, P < 0.0001). The analysis was extended to the whole number of weak p24 antibody reactors (n = 311) of the other 13 farms. The mean of high PVL reactors within weak p24 reactors was 17.38% (SD = 8.92). In 5/15 farms, the number of weak p24 reactors with high PVL was lower than 10%. We found that the humoral response reflected the level of in vivo infection, and may therefore have useful epidemiological applications. Whereas the quantitative evaluation of blood proviral load using real-time PCR is expensive and technically demanding, the measurement of antibodies in blood by ELISA is relatively straightforward and could therefore constitute a cost-effective tool in a BLV control intervention strategy, especially in highly infected herds such as Argentinean dairy ones.


Combining miRNA and mRNA Expression Profiles in Wilms Tumor Subtypes.
Wilms tumor (WT) is the most common childhood renal cancer. Recent findings of mutations in microRNA (miRNA) processing proteins suggest a pivotal role of miRNAs in WT genesis. We performed miRNA expression profiling of 36 WTs of different subtypes and four normal kidney tissues using microarrays. Additionally, we determined the gene expression profile of 28 of these tumors to identify potentially correlated target genes and affected pathways. We identified 85 miRNAs and 2107 messenger RNAs (mRNA) differentially expressed in blastemal WT, and 266 miRNAs and 1267 mRNAs differentially expressed in regressive subtype. The hierarchical clustering of the samples, using either the miRNA or mRNA profile, showed the clear separation of WT from normal kidney samples, but the miRNA pattern yielded better separation of WT subtypes. A correlation analysis of the deregulated miRNA and mRNAs identified 13,026 miRNA/mRNA pairs with inversely correlated expression, of which 2844 are potential interactions of miRNA and their predicted mRNA targets. We found significant upregulation of miRNAs-183, -301a/b and -335 for the blastemal subtype, and miRNAs-181b, -223 and -630 for the regressive subtype. We found marked deregulation of miRNAs regulating epithelial to mesenchymal transition, especially in the blastemal subtype, and miRNAs influencing chemosensitivity, especially in regressive subtypes. Further research is needed to assess the influence of preoperative chemotherapy and tumor infiltrating lymphocytes on the miRNA and mRNA patterns in WT.


Neurocognitive Trajectory of Boys Who Received a Hematopoietic Stem Cell Transplant at an Early Stage of Childhood Cerebral Adrenoleukodystrophy.
Untreated childhood cerebral adrenoleukodystrophy (cALD) is a fatal disease associated with progressive cerebral demyelination and rapid, devastating neurologic decline. The standard of care to enhance long-term survival and stabilize cerebral disease is a hematopoietic stem cell transplant (HSCT). Neurologic outcomes are better when HSCT occurs at an earlier stage of cALD, yet there is limited understanding of the neurocognitive trajectory of patients who undergo HSCT. To characterize neurocognitive outcomes of boys with cALD and early-stage cerebral disease who were treated with an allogeneic HSCT and to identify disease- and treatment-related factors associated with long-term functioning. Baseline and follow-up neurocognitive test performance was analyzed for all boys with cALD who received an HSCT at the University of Minnesota between January 1, 1991, and October 20, 2014, and who had a pretransplant magnetic resonance imaging (MRI) severity score of less than 10 (scale range, 0-34; higher scores indicate greater severity). Longitudinal neurocognitive test performance in 4 domains (verbal comprehension, perceptual [visual] reasoning, working memory, and processing speed) were the primary outcome measures. Secondary analysis at the most recent evaluation also included measures of sustained attention, verbal memory, visual-motor integration, and fine motor function. Among the 62 boys in this study (mean [SD] age at transplant, 8.37 [2.80] years; range, 4-16 years), there was a significant association of pretransplant MRI severity and baseline verbal comprehension (r = -0.340; P = .008), perceptual reasoning (r = -0.419; P = .001), and processing speed (r = -0.285; P = .03) scores. Higher pretransplant MRI severity scores were also associated with a steeper decline in neurocognitive functioning during the 5-year follow-up period. Twenty-two of 33 patients (67%) with available long-term follow-up neurocognitive testing had severe impairment in at least 1 neurocognitive domain at the most recent evaluation. Boys with cALD who have greater than minimal cerebral disease detected on MRI scans at the time of an HSCT are at risk for severe, persistent neurocognitive deficits. These findings motivate further exploration of methods of detecting cerebral disease prior to development of lesions observable on MRI scans, an endeavor that may be facilitated by newborn screening for adrenoleukodystrophy. These findings may serve a benchmark role in evaluating the efficacy of novel interventions for cALD.


Effect of breast augmentation on the accuracy of mammography and cancer characteristics.
Breast augmentation is not associated with an increased risk of breast cancer; however, implants may interfere with the detection of breast cancer thereby delaying cancer diagnosis in women with augmentation. To determine whether mammography accuracy and tumor characteristics are different for women with and without augmentation. A prospective cohort of 137 women with augmentation and 685 women without augmentation diagnosed with breast cancer between January 1, 1995, and October 15, 2002, matched (1:5) by age, race/ethnicity, previous mammography screening, and mammography registry, and 10 533 women with augmentation and 974 915 women without augmentation and without breast cancer among 7 mammography registries in Denver, Colo; Lebanon, NH; Albuquerque, NM; Chapel Hill, NC; San Francisco, Calif; Seattle, Wash; and Burlington, Vt. Comparison between women with and without augmentation of mammography performance measures and cancer characteristics, including invasive carcinoma or ductal carcinoma in situ, tumor stage, nodal status, size, grade, and estrogen-receptor status. Among asymptomatic women, the sensitivity of screening mammography based on the final assessment was lower in women with breast augmentation vs women without (45.0% [95% confidence interval [CI], 29.3%-61.5%] vs 66.8% [95% CI, 60.4%-72.8%]; P =.008), and specificity was slightly higher in women with augmentation (97.7% [95% CI, 97.4%-98.0%] vs 96.7% [95% CI, 96.6%-96.7%]; P<.001). Among symptomatic women, both sensitivity and specificity were lower for women with augmentation compared with women without but these differences were not significant. Tumors were of similar stage, size, estrogen-receptor status, and nodal status but tended to be lower grade (P =.052) for women with breast augmentation vs without. Breast augmentation decreases the sensitivity of screening mammography among asymptomatic women but does not increase the false-positive rate. Despite the lower accuracy of mammography in women with augmentation, the prognostic characteristics of tumors are not influenced by augmentation.


Public Health Strategies to Prevent Genital Herpes: Where Do We Stand?
At least 25% of the United States population has overt or subclinical genital herpes simplex virus (HSV) infection, and herpes probably is the sexually transmitted disease of greatest concern to sexually active persons, aside from AIDS. In addition to its direct clinical and psychosexual complications, genital herpes is an important determinant of sexual transmission of HIV. Genital herpes is usually transmitted by persons with subclinical infection, whether entirely asymptomatic or with unrecognized symptoms. Although the composition and efficacy of a national genital herpes prevention program are in debate, clinicians should adopt a public health perspective in managing patients to help prevent transmission. Specific approaches include accurate diagnosis of genital ulcer disease by routine use of virologic tests for HSV; use of type-specific serologic tests to diagnose subclinical HSV infection in patients' sex partners and others at high risk; counseling patients to recognize symptoms and defer sex with uninfected partners when symptomatic; and serologic testing and counseling of pregnant women and their partners to prevent neonatal herpes. Antiviral chemotherapy may be effective in preventing herpes-related cesarean sections, and its efficacy in preventing sexual transmission of HSV is under study.


Structure and assembly mechanism for heteromeric kainate receptors.
Native glutamate receptor ion channels are tetrameric assemblies containing two or more different subunits. NMDA receptors are obligate heteromers formed by coassembly of two or three divergent gene families. While some AMPA and kainate receptors can form functional homomeric ion channels, the KA1 and KA2 subunits are obligate heteromers which function only in combination with GluR5-7. The mechanisms controlling glutamate receptor assembly involve an initial step in which the amino terminal domains (ATD) assemble as dimers. Here, we establish by sedimentation velocity that the ATDs of GluR6 and KA2 coassemble as a heterodimer of K(d) 11 nM, 32,000-fold lower than the K(d) for homodimer formation by KA2; we solve crystal structures for the GluR6/KA2 ATD heterodimer and heterotetramer assemblies. Using these structures as a guide, we perform a mutant cycle analysis to probe the energetics of assembly and show that high-affinity ATD interactions are required for biosynthesis of functional heteromeric receptors.


An open-source representation for 2-DE-centric proteomics and support infrastructure for data storage and analysis.
In spite of two-dimensional gel electrophoresis (2-DE) being an effective and widely used method to screen the proteome, its data standardization has still not matured to the level of microarray genomics data or mass spectrometry approaches. The trend toward identifying encompassing data standards has been expanding from genomics to transcriptomics, and more recently to proteomics. The relative success of genomic and transcriptomic data standardization has enabled the development of central repositories such as GenBank and Gene Expression Omnibus. An equivalent 2-DE-centric data structure would similarly have to include a balance among raw data, basic feature detection results, sufficiency in the description of the experimental context and methods, and an overall structure that facilitates a diversity of usages, from central reposition to local data representation in LIMs systems. Achieving such a balance can only be accomplished through several iterations involving bioinformaticians, bench molecular biologists, and the manufacturers of the equipment and commercial software from which the data is primarily generated. Such an encompassing data structure is described here, developed as the mature successor to the well established and broadly used earlier version. A public repository, AGML Central, is configured with a suite of tools for the conversion from a variety of popular formats, web-based visualization, and interoperation with other tools and repositories, and is particularly mass-spectrometry oriented with I/O for annotation and data analysis.


COMPULS: design of a multicenter phenotypic, cognitive, genetic, and magnetic resonance imaging study in children with compulsive syndromes.
Compulsivity, the closely linked trait impulsivity and addictive behaviour are associated with several neurodevelopmental disorders, including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive compulsive disorder (OCD). All three disorders show impaired fronto-striatal functioning, which may be related to altered glutamatergic signalling. Genetic factors are also thought to play an important role in the aetiology of compulsivity-related disorders. The COMPULS study is a multi-center study designed to investigate the relationship between the traits compulsivity, impulsivity, and, to a lesser extent, addictive behaviour within and across the neurodevelopmental disorders ADHD, ASD, and OCD. This will be done at the phenotypic, cognitive, neural, and genetic level. In total, 240 participants will take part in COMPULS across four different sites in Europe. Data collection will include diagnostic interviews, behavioural questionnaires, cognitive measures, structural, functional and spectral neuroimaging, and genome-wide genetic information. The COMPULS study will offer the unique opportunity to investigate several key aspects of compulsivity across a large cohort of ADHD, ASD and OCD patients.