Correlation of imaging and histopathology of thrombi in acute ischemic stroke with etiology and outcome: a systematic review.
Studying the imaging and histopathologic characteristics of thrombi in ischemic stroke could provide insights into stroke etiology and ideal treatment strategies. We conducted a systematic review of imaging and histologic characteristics of thrombi in acute ischemic stroke. We identified all studies published between January 2005 and December 2015 that reported findings related to histologic and/or imaging characteristics of thrombi in acute ischemic stroke secondary to large vessel occlusion. The five outcomes examined in this study were (1) association between histologic composition of thrombi and stroke etiology; (2) association between histologic composition of thrombi and angiographic outcomes; (3) association between thrombi imaging and histologic characteristics; (4) association between thrombi imaging characteristics and angiographic outcomes; and (5) association between imaging characteristics of thrombi and stroke etiology. A meta-analysis was performed using a random effects model. There was no significant difference in the proportion of red blood cell (RBC)-rich thrombi between cardioembolic and large artery atherosclerosis etiologies (OR 1.62, 95% CI 0.1 to 28.0, p=0.63). Patients with a hyperdense artery sign had a higher odds of having RBC-rich thrombi than those without a hyperdense artery sign (OR 9.0, 95% CI 2.6 to 31.2, p<0.01). Patients with a good angiographic outcome had a mean thrombus Hounsfield unit (HU) of 55.1±3.1 compared with a mean HU of 48.4±1.9 for patients with a poor angiographic outcome (mean standard difference 6.5, 95% CI 2.7 to 10.2, p<0.001). There was no association between imaging characteristics and stroke etiology (OR 1.13, 95% CI 0.32 to 4.00, p=0.85). The hyperdense artery sign is associated with RBC-rich thrombi and improved recanalization rates. However, there was no association between the histopathological characteristics of thrombi and stroke etiology and angiographic outcomes.


Geminin cooperates with Polycomb to restrain multi-lineage commitment in the early embryo.
Transient maintenance of a pluripotent embryonic cell population followed by the onset of multi-lineage commitment is a fundamental aspect of development. However, molecular regulation of this transition is not well characterized in vivo. Here, we demonstrate that the nuclear protein Geminin is required to restrain commitment and spatially restrict mesoderm, endoderm and non-neural ectoderm to their proper locations in the Xenopus embryo. We used microarray analyses to demonstrate that Geminin overexpression represses many genes associated with cell commitment and differentiation, while elevating expression levels of genes that maintain pluripotent early and immature neurectodermal cell states. We characterized the relationship of Geminin to cell signaling and found that Geminin broadly represses Activin-, FGF- and BMP-mediated cell commitment. Conversely, Geminin knockdown enhances commitment responses to growth factor signaling and causes ectopic mesodermal, endodermal and epidermal fate commitment in the embryo. We also characterized the functional relationship of Geminin with transcription factors that had similar activities and found that Geminin represses commitment independent of Oct 4 ortholog (Oct25/60) activities, but depends upon intact Polycomb repressor function. Consistent with this, chromatin immunoprecipitation assays directed at mesodermal genes demonstrate that Geminin promotes Polycomb binding and Polycomb-mediated repressive histone modifications, while inhibiting modifications associated with gene activation. This work defines Geminin as an essential regulator of the embryonic transition from pluripotency through early multi-lineage commitment, and demonstrates that functional cooperativity between Geminin and Polycomb contributes to this process.


A global analysis of matches and mismatches between human genetic and linguistic histories.
Human history is written in both our genes and our languages. The extent to which our biological and linguistic histories are congruent has been the subject of considerable debate, with clear examples of both matches and mismatches. To disentangle the patterns of demographic and cultural transmission, we need a global systematic assessment of matches and mismatches. Here, we assemble a genomic database (GeLaTo, or Genes and Languages Together) specifically curated to investigate genetic and linguistic diversity worldwide. We find that most populations in GeLaTo that speak languages of the same language family (i.e., that descend from the same ancestor language) are also genetically highly similar. However, we also identify nearly 20% mismatches in populations genetically close to linguistically unrelated groups. These mismatches, which occur within the time depth of known linguistic relatedness up to about 10,000 y, are scattered around the world, suggesting that they are a regular outcome in human history. Most mismatches result from populations shifting to the language of a neighboring population that is genetically different because of independent demographic histories. In line with the regularity of such shifts, we find that only half of the language families in GeLaTo are genetically more cohesive than expected under spatial autocorrelations. Moreover, the genetic and linguistic divergence times of population pairs match only rarely, with Indo-European standing out as the family with most matches in our sample. Together, our database and findings pave the way for systematically disentangling demographic and cultural history and for quantifying processes of shifts in language and social identities on a global scale.


Effectiveness of complex falls prevention interventions in residential aged care settings: a systematic review.
The objective of this review was to synthesize the best available evidence for the effectiveness of complex falls prevention interventions delivered at two or more of the following levels: resident, facility or organization, on fall rates in the residential aged care (RAC) population. Preventing falls in the high risk RAC population is a common global goal with acknowledged complexity. Previous meta-analyses have not specifically addressed complexity, described as falls prevention intervention delivery at multiple levels of a RAC organization, to determine its effect on fall outcomes. The current review considered studies that included participants who were aged 65 years and over residing in long-term care settings providing 24-hour supervision and/or care assistance.Studies that evaluated complex falls prevention interventions delivered by single discipline or multidisciplinary teams across at least two or all of the following levels: residents, RAC facility and RAC organization were eligible. Experimental study designs including randomized controlled trials, controlled clinical trials and quasi-experimental trials that reported on measures related to fall incidence were considered, namely, rate of falls (expressed as the number of falls per 1000 occupied bed days), the number of participants who became fallers (expressed as the number of participants who fell once or more) and the rate of injurious falls (expressed as the number of falls with injury per 1000 occupied bed days). A three-step search strategy was undertaken, commencing with an initial scoping search of MEDLINE and CINAHL databases prior to an extensive search of all relevant published literature, clinical trial registries and gray literature. Two independent reviewers assessed selected studies for methodological validity using the standardized critical appraisal instrument from the Joanna Briggs Institute System for the Unified Management, Assessment and Review of Information (JBI SUMARI). Data were extracted from the selected studies using the standardized data extraction tool from JBI SUMARI. Quantitative data were pooled in statistical meta-analysis for rate of falls, the number of participants who became fallers and the rate of injurious falls. Meta-analysis was conducted using a random-effect model with heterogeneity assessed using the standard Chi-squared and I index. Where statistical pooling was not possible, study findings were presented in narrative form. Twelve studies were included in this review with seven being eligible for meta-analysis. Complex falls prevention interventions delivered at multiple levels in RAC populations did not show a significant effect in reducing fall rates (MD = -1.29; 95% CI [-3.01, 0.43]), or the proportion of residents who fell (OR = 0.76; 95% CI [0.42, 1.38]). However, a sensitivity analysis suggested complex falls prevention interventions delivered with additional resources at multiple levels had a significant positive effect in reducing fall rates (MD = -2.26; 95% CI [-3.72, -0.80]). Complex falls prevention interventions delivered at multiple levels in the RAC population may reduce fall rates when additional staffing, expertise or resources are provided. Organizations may need to determine how resources can be allocated to best address falls prevention management. Future research should continue to investigate which combinations of multifactorial interventions are effective.


Synthesis and characterization of iron oxide-coated silica and its effect on metal adsorption.
To accurately model metal mobility and bioavailability in soils and sediments, systematic adsorption studies are needed in considering heterogeneous, well characterized minerals. Two important surfaces are iron oxide and silica, which are ubiquitous and associated with one another in the environment playing important roles in metal distribution. This study focuses on the synthesis and characterization of such a system, iron oxide-coated silica. A three-level fractional factorial study was used to determine the optimum conditions for producing goethite-coated silica. The amount of coating achieved was between 0.59 and 21.36 mg Fe g(-1) solid. The most significant factor in coating using either adsorption or precipitation was the particle size of silica, where Fe increased from an average of 0.85 to 9.6 mg Fe g(-1) solid as silica size decreased from 1.5 to 0.2 mm. Other factors investigated, including coating temperature, initial iron concentration, and contact time, were of less importance. The iron oxide coatings were observed to be non-uniform, concentrated in rough concave areas. FTIR revealed a band shift as well as a new band indicating changes in the chemical environment of FeO and SiO bonds; these results along with abrasion studies suggest that the interaction between the oxide coating and silica surface potentially involves chemical forces. Because the nano-sized iron oxide coatings increased surface area, introduced small pores, and changed the surface charge distribution of silica, the coated system demonstrates a greater affinity for Ni compared to that of uncoated silica.


Optimizing a low-energy electron diffraction spin-polarization analyzer for imaging of magnetic surface structures.
A newly designed scanning electron microscope with polarization analysis (SEMPA or spin-SEM) for the acquisition of magnetic images is presented. Core component is the spin detector, based on the scattering of low-energy electrons at a W(100) surface in ultrahigh vacuum. The instrument has been optimized with respect to ease of handling and efficiency. The operation and performance of a general low-energy electron diffraction (LEED) detector for SEMPA have been modeled in order to find the optimum operating parameters and to predict the obtainable image asymmetry. Based on the energy dependence of the secondary electron polarization and intensity, the detector output is simulated. For our instrument with optimized performance we demonstrate experimentally 8.6% polarization asymmetry in the domain structure of an iron whisker. This corresponds to 17.2% image contrast, in excellent agreement with the predicted simulated value. A contrast to noise ratio of 27 is achieved at 5 ms acquisition time per pixel.


Coping with discrimination among Mexican American college students.
There is limited research directly examining the process of how Mexican American college students cope with unique experiences of racial discrimination. The present study used a multiple mediation model to collectively examine the indirect effects of engagement (i.e., problem solving, cognitive restructuring, expression of emotion, and social support) and disengagement (i.e., social withdrawal, self-criticism, problem avoidance, and wishful thinking) coping strategies on the relationship between perceived racial discrimination and subjective well-being of 302 Mexican American college students. Results suggested that perceived racial discrimination was negatively correlated with subjective well-being. Moreover, of the engagement coping strategies examined, only problem solving had a significant mediating effect that was associated with elevations in subjective well-being. Specifically, perceptions of racial discrimination were positively related to problem solving, which, in turn, was positively related to subjective well-being. Of the disengagement coping strategies examined, self-criticism, wishful thinking, and social withdrawal had a significant mediating effect that was negatively associated with subjective well-being. Specifically, perceptions of racial discrimination were positively related to self-criticism, wishful thinking, and social withdrawal, which, in turn, were negatively related to subjective well-being. Ultimately, these findings highlight the indirect and complex ways in which multiple coping strategies are used to effectively, and sometimes not effectively, deal with racism experienced by Mexican Americans college students.


Evaluating an Integrative Theoretical Framework for HIV Sexual Risk among Juvenile Justice involved Adolescents.
Juvenile justice involved youth are at great risk for negative outcomes of risky sexual behavior including HIV/AIDS. Given the strong connection between alcohol use and risky sex in this population, it is important to consider alcohol use in interventions designed to decrease risky sexual behavior. This paper provides support for an integrative translational model that incorporates psychosocial, neurobiological, and genetic factors to better predict alcohol-related sexual risk behavior. Specifically, we present the design, methods, and baseline data from a complex randomized control trial, Project SHARP (Sexual Health and Adolescent Risk Prevention) in order to illustrate how this broad array of factors can best predict alcohol-related sexual risk behavior. Participants were justice-involved adolescents (n=284) who completed an fMRI and self-report assessments prior to randomization to either a sexual risk plus alcohol risk reduction group intervention or to an information-only contact control group intervention. Structural equation modeling was utilized and findings supported the hypothesized relationships in the translational model. Preliminary data suggest that interventions among justice-involved adolescents targeting alcohol-related sexual risk behavior may be more effective if a biopsychosocial approach is considered.


Successful treatment of refractory pudendal neuralgia with pulsed radiofrequency.
Pudendal neuralgia (PN) involves severe, sharp pain along the course of the pudendal nerve, often aggravated with sitting. Current therapies include medication management, nerve blocks, decompression surgery, and neuromodulation. The ideal management for PN has not been determined. We present a case of a female with 1.5 years of sharp, burning pain of the left gluteal and perineal regions. She could not sit for longer than 10 to 15 minutes. Sacroiliac joint, epidural, and piriformis injections did not improve her pain. She had tried physical therapy, occupational therapy, massage, and acupuncture but the pain persisted. Medication treatment with oxycodone-acetaminophen, extended release morphine sulfate, amitriptyline, and gabapentin provided only minor relief and she had failed other multianalgesic therapy. She had been unable to work at her desk job for over a year. She had a positive response to 2 diagnostic pudendal nerve blocks with lidocaine that provided pain relief for several hours. This patient elected to undergo pulsed radiofrequency (PRF) of the left pudendal nerve in hopes of achieving a longer duration and improved pain relief. PRF was carried out at a frequency of 2 Hz and a pulse width of 20 milliseconds for a duration of 120 seconds at 42 degrees Celsius. After the procedure she reported tolerating sitting for 4 to 5 hours. Her multianalgesic therapy was successfully weaned. At 5 months follow-up she felt motivated to return to work. One and a half years after the procedure the patient is only taking oxycodone-acetaminophen for pain relief and still has good sitting tolerance. There were no procedure-related complications. To our knowledge PRF for the treatment of PN has not been reported elsewhere in the literature. PRF is a relatively new procedure and is felt to be safer than continuous radiofrequency. Current literature suggests that PRF delivers an electromagnetic field, which modifies neuro-cellular function with minimal cellular destruction. We conclude that PRF of the pudendal nerve offers promise as a potential treatment of PN that is refractory to conservative therapy.


Five-Year Outcomes After Vertical Sleeve Gastrectomy for Severe Obesity: A Prospective Cohort Study.
We present 5-year outcomes after vertical sleeve gastrectomy (VSG), including complications and revisions, weight change, obesity-related diseases and health-related quality of life (HRQOL). Patients operated from December 2005 to November 2010 were included. All variables except HRQOL (obtained using Short Form-36) were assessed prospectively. HRQOL data was assessed cross-sectionally, comparing 5-year results to both a baseline cohort of severely obese patients prior to bariatric surgery and to Norwegian norms. Of 168 operated patients (mean age, 40.3 ± 10.5 years; 71% females), 92% completed 2-year and 82% 5-year follow-up. Re-intervention for complications occurred in four patients, whereas revision surgery was performed in six patients for weight regain and in one patient for gastroesophageal reflux disease (GERD). Mean body mass index (BMI) decreased from 46.2 ± 6.4 kg/m2 at baseline to 30.5 ± 5.8 kg/m2 at 2 years and 32.9 ± 6.1 kg/m2 at 5 years. Remission of type 2 diabetes mellitus (T2DM) and hypertension occurred in 79 and 62% at 2 years, and 63 and 60% at 5 years, respectively. The percentage of patients treated for GERD increased from 12% preoperatively to 29% at 2 years and 35% at 5 years. The physical and mental SF-36 summary scores showed significantly better HRQOL at 5 years compared with the baseline cohort, but did not reach population norms. The majority of VSG patients maintained successful weight loss and improvement of T2DM, hypertension and HRQOL at 5 years. Preventing weight regain and GERD are important considerations with this procedure.


Choosing Important Health Outcomes for Comparative Effectiveness Research: An Updated Review and User Survey.
A COS represents an agreed minimum set of outcomes that should be measured and reported in all trials of a specific condition. The COMET (Core Outcome Measures in Effectiveness Trials) initiative aims to collate and stimulate the development and application of COS, by including data on relevant studies within a publically available internet-based resource. In recent years, there has been an interest in increasing the development of COS. Therefore, this study aimed to provide an update of a previous review, and examine the quality of development of COS. A further aim was to understand the reasons why individuals are searching the COMET database. A multi-faceted search strategy was followed, in order to identify studies that sought to determine which outcomes/domains to measure in clinical trials of a specific condition. Additionally, a pop up survey was added to the COMET website, to ascertain why people were searching the COMET database. Thirty-two reports relating to 29 studies were eligible for inclusion in the review. There has been an improvement in the description of the scope of a COS and an increase in the proportion of studies using literature/systematic reviews and the Delphi technique. Clinical experts continue to be the most common group involved in developing COS, however patient and public involvement has increased. The pop-up survey revealed the most common reasons for visiting the COMET website to be thinking about developing a COS and planning a clinical trial. This update demonstrates that recent studies appear to have adopted a more structured approach towards COS development and public representation has increased. However, there remains a need for developers to adequately describe details about the scope of COS, and for greater public engagement. The COMET database appears to be a useful resource for both COS developers and users of COS.


The emergence, implementation, and future growth of pharmacogenomics in psychiatry: a narrative review.
Psychotropic medication efficacy and tolerability are critical treatment issues faced by individuals with psychiatric disorders and their healthcare providers. For some people, it can take months to years of a trial-and-error process to identify a medication with the ideal efficacy and tolerability profile. Current strategies (e.g. clinical practice guidelines, treatment algorithms) for addressing this issue can be useful at the population level, but often fall short at the individual level. This is, in part, attributed to interindividual variation in genes that are involved in pharmacokinetic (i.e. absorption, distribution, metabolism, elimination) and pharmacodynamic (e.g. receptors, signaling pathways) processes that in large part, determine whether a medication will be efficacious or tolerable. A precision prescribing strategy know as pharmacogenomics (PGx) assesses these genomic variations, and uses it to inform selection and dosing of certain psychotropic medications. In this review, we describe the path that led to the emergence of PGx in psychiatry, the current evidence base and implementation status of PGx in the psychiatric clinic, and finally, the future growth potential of precision psychiatry via the convergence of the PGx-guided strategy with emerging technologies and approaches (i.e. pharmacoepigenomics, pharmacomicrobiomics, pharmacotranscriptomics, pharmacoproteomics, pharmacometabolomics) to personalize treatment of psychiatric disorders.


High frequency of human enterovirus species C circulation in Madagascar.
Four poliomyelitis outbreaks caused by vaccine-derived polioviruses have been reported recently, including one in Madagascar in 2002. In all cases, the viral strains involved were recombinant between poliovirus vaccine strains and nonpoliovirus strains, probably enterovirus species C. Nevertheless, little is known about the circulation and epidemiology of enteroviruses in the regions where these outbreaks occurred. To assess the circulation of enteroviruses (particularly enterovirus species C) in Madagascar, we genetically characterized 55 enterovirus strains isolated between 1994 and 2002. The strains were identified and compared by partially sequencing the region encoding the VP1 capsid protein. Phylogenetic analysis and pairwise comparison with prototype enterovirus strains distinguished two different species: 25 isolates belonged to human enterovirus B species, and 30 isolates were identified as coxsackievirus A13, A15, A17, A18, A20, A21, and A24, belonging to the human enterovirus species C. The relatively high frequency and the wide distribution of species C coxsackie A viruses in different regions of Madagascar suggest that they had been silently and widely circulating in the country during the whole study period. The circulation of coxsackie A viruses, combined with the low routine oral polio vaccine coverage, may have played a role in the emergence of the recent outbreak in Madagascar.


'We hold these truths to be self-evident': deconstructing 'evidence-based' medical practice.
Rationale, aims and objectives Evidence-based medicine (EBM) claims to be based on 'evidence', rather than 'intuition'. However, EBM's fundamental distinction between quantitative 'evidence' and qualitative 'intuition' is not self-evident. The meaning of 'evidence' is unclear and no studies of quality exist to demonstrate the superiority of EBM in health care settings. This paper argues that, despite itself, EBM holds out only the illusion of conclusive scientific rigour for clinical decision making, and that EBM ultimately is unable to fulfil its own structural criteria for 'evidence'. Methods Our deconstructive analysis of EBM draws on the work of the French philosopher, Jacques Derrida. Deconstruction works in the name of justice to lay bare, to expose what has been hidden from view. In plain language, we deconstruct EBM's paradigm of 'evidence', the randomized controlled trial (RCT), to demonstrate that there cannot be incontrovertible evidence for EBM as such. We argue that EBM therefore 'auto-deconstructs' its own paradigm, and that medical practitioners, policymakers and patients alike ought to be aware of this failure within EBM itself. Results EBM's strict distinction between admissible evidence (based on RCTs) and other supposedly inadmissible evidence is not itself based on evidence, but rather, on intuition. In other words, according to EBM's own logic, there can be no 'evidentiary' basis for its distinction between admissible and inadmissible evidence. Ultimately, to uphold this fundamental distinction, EBM must seek recourse in (bio)political ideology and an epistemology akin to faith.


A mobile-phone based high-resolution microendoscope to image cervical precancer.
Nearly 90% of cervical cancer cases and deaths occur in low- and middle-income countries that lack comprehensive national HPV immunization and cervical cancer screening programs. In these settings, it is difficult to implement screening programs due to a lack of infrastructure and shortage of trained personnel. Screening programs based on visual inspection with acetic acid (VIA) have been successfully implemented in some low-resource settings. However, VIA has poor specificity and up to 90% of patients receiving treatment based on a positive VIA exam are over-treated. A number of studies have suggested that high-resolution cervical imaging to visualize nuclear morphology in vivo can improve specificity by better distinguishing precancerous and benign lesions. To enable high-resolution imaging in low-resource settings, we developed a portable, low-cost, high-resolution microendoscope that uses a mobile phone to detect and display images of cervical epithelium in vivo with subcellular resolution. The device was fabricated for less than $2,000 using commercially available optical components including filters, an LED and triplet lenses assembled in a 3D-printed opto-mechanical mount. We show that the mobile high-resolution microendoscope achieves similar resolution and signal-to-background ratio as previously reported high-resolution microendoscope systems using traditional cameras and computers to detect and display images. Finally, we demonstrate the ability of the mobile high-resolution microendoscope to image normal and precancerous squamous epithelium of the cervix in vivo in a gynecological referral clinic in Barretos, Brazil.


Asbestos exposure and posttraumatic stress disorder.
In 48 cases of claims of psychic injury due to exposure to asbestos, posttraumatic stress disorder (PTSD) was alleged as a basis for damages in nine (19%). PTSD as currently defined refers to a specific syndrome following exposure to a life-threatening traumatic event, one outside the general range of people's experiences such as military combat, floods, earthquakes, bombing, torture, death camps--events either natural or man-made. The symptoms include reexperiencing of the event with intrusive thoughts or nightmares of the event, startle reactions, psychic numbing, and survival guilt. The application of this concept to chronic illness, often of minor degree, is quite inappropriate. The clinical data in the nine cases reveal no pertinent precipitating event and the lack of a clinical syndrome compatible with the disorder. The cases also generally reflect no psychiatric impairment, inadequate medical review, and lack of background history--common characteristics in asbestos litigation with no disabling pulmonary parenchymal impairment. If the results in this group are typical, then one must suspect the legitimacy of claims of psychic injury such as post-traumatic stress disorder from asbestos exposure and at the very least the reasonableness of the experts who provide input into the medicolegal process.


Visualization of plant viral suppressor silencing activity in intact leaf lamina by quantitative fluorescent imaging.
Transient expression of proteins in plants has become a favoured method over the production of stably transformed plants because, in addition to enabling high protein yields, it is both fast and easy to apply. An enhancement of transient protein expression can be achieved by plant virus-encoded RNA silencing suppressor proteins. Since viral suppressor proteins differ in their efficiency to enhance transient protein expression in plants, we developed a whole-leaf green fluorescent protein (GFP)-based imaging assay to quantitatively assess suppressor protein activity. In a transient GFP-expression assay using wild-type and GFP-transgenic N. benthamiana, addition of the plant viral suppressors Beet mild yellowing virus (BMYV-IPP) P0 or Plum pox virus (PPV) HC-Pro was shown to increase fluorescent protein expression 3-4-fold, 7 days post inoculation (dpi) when compared to control plants. In contrast, in agroinfiltrated patches without suppressor activity, near complete silencing of the GFP transgene was observed in the transgenic N. benthamiana at 21 dpi. Both co-infiltrated suppressors significantly enhanced GFP expression over time, with HC-Pro co-infiltrations leading to higher short term GFP fluorescence (at 7 dpi) and P0 giving higher long term GFP fluorescence (at 21 dpi). Additionally, in contrast to HC-Pro co-infiltrations, an area of complete GFP silencing was observed at the edge of P0 co-infiltrated areas. Fluorescence imaging of whole intact leaves proved to be an easy and effective method for spatially and quantitatively observing viral suppressor efficiency in plants. This suppressor assay demonstrates that plant viral suppressors greatly enhanced transient GFP expression, with P0 showing a more prolonged suppressor activity over time than HC-Pro. Both suppressors could prove to be ideal candidates for enhancing target protein expression in plants.


Resistance to Phytophthora nicotianae in Tobacco Breeding Lines Derived from Variety Beinhart 1000.
Black shank, caused by Phytophthora nicotianae, is managed primarily by host resistance. The rapid emergence of race 1 eliminated the usefulness of available complete resistance, leading breeders to search for new sources of resistance. Cigar tobacco 'Beinhart 1000' (BH) is highly resistant to all races of P. nicotianae. Doubled-haploid (DH) lines from a cross of BH and the susceptible 'Hicks' were evaluated for black shank resistance, and quantitative trait loci (QTL) on linkage groups (LGs) 4 and 8 accounted for >43% of the phenotypic variation in resistance. Forty-three DH lines and parents were evaluated, and genotypes with one or both QTL from BH on LGs 4 and 8 had increased incubation periods and decreased root rot but higher final inoculum levels than genotypes with neither QTL. A low level of stem resistance was observed in BH and DH lines with the QTL from BH on LG 4 but not LG 8. Low levels of leaf resistance were seen for Hicks, BH, and DH lines with both QTL from BH on LG 4 and 8. The partial resistance from BH has not been used commercially and may provide an increase in level of partial resistance in future tobacco varieties.


Nature and timing of incidents intercepted by the SURPASS checklist in surgical patients.
More than half of in-hospital adverse events can be attributed to a surgical discipline. Checklists can effectively decrease errors and adverse events. However, the mechanisms by which checklists lead to increased safety are unclear. This study aimed to assess the number, nature and timing of incidents intercepted by use of the Surgical Patient Safety System (SURPASS) checklist, a patient-specific multidisciplinary checklist that covers the entire surgical patient pathway. The checklist was implemented in two academic hospitals and four teaching hospitals in the Netherlands. Users of the checklist had three options for each item that was checked: 'not applicable', 'yes' and 'intercepted by checklist'. In each hospital, the first 1000 completed checklists were entered into an online central database. In six participating hospitals, 6313 checklists were collected. One or more incidents were intercepted in 2562 checklists (40.6%). In total, 6312 incidents were intercepted. After correction for the number of items and the extent of adherence in each part of the checklist, the number of intercepted incidents was highest in the preoperative and postoperative stages. The checklist intercepts many potentially harmful incidents across all stages of the surgical patient pathway. The majority of incidents were intercepted in the preoperative and postoperative stages of the pathway. The degree to which these incidents would have been intercepted by a single checklist in the operating room only, compared with a checklist for the entire surgical pathway, remains a subject for future study.


The Longitudinal Relation Between Accumulation of Adverse Life Events and Body Mass Index From Early Adolescence to Young Adulthood.
Stressors, such as adverse life events, can cause weight changes through behavioral and biological mechanisms. Whether the accumulation of adverse life events is related to body mass index (BMI) across multiple time points from early adolescence to young adulthood has not been investigated to date. Data are from 2188 children participating at T1 (10-12 years), T3 (14-18 years), and/or T5 (21-23 years) of the prospective Tracking Adolescents' Individual Lives Survey cohort study. Adverse events before T1 and between T1, T3, and T5 were measured with a parent interview at T1 and a semistructured interview (Event History Calendar) with the adolescent at T3 and T5. An adverse events score was calculated per wave. Body mass index z-scores were determined from objectively measured height and weight using the LMS (skewness, median, and coefficient of variation) reference curves of the International Obesity Task Force for children 18 years or younger. Data were analyzed using a modified bivariate autoregressive cross-lagged structural equation model. Adverse events before T1 and between T3 and T5 were related to BMI at T5 (β = 0.06, p = .001 and β = -0.04, p = .04, respectively). Specifically, health events before T1 were associated with a higher BMI at T5, and events related to relationships and victimhood events between T3 and T5 were associated with a lower BMI at T5. Adverse relationship and victimhood events in their recent past were related to a lower BMI in young adults, whereas adverse health events during childhood were related to a higher BMI in young adults. No relationships were found between adverse life events with BMI in children and adolescents.


Goosecoid acts cell autonomously in mesenchyme-derived tissues during craniofacial development.
Mice homozygous for a targeted deletion of the homeobox gene Goosecoid (Gsc) have multiple craniofacial defects. To understand the mechanisms responsible for these defects, the behavior of Gsc-null cells was examined in morula aggregation chimeras. In these chimeras, Gsc-null cells were marked with beta-galactosidase (beta-gal) activity using the ROSA26 lacZ allele. In addition, mice with a lacZ gene that had been introduced into the Gsc locus were used as a guide to visualize the location of Gsc-expressing cells. In Gsc-null<->wild-type chimeras, tissues that would normally not express Gsc were composed of both Gsc-null and wild-type cells that were well mixed, reflecting the overall genotypic composition of the chimeras. However, craniofacial tissues that would normally express Gsc were essentially devoid of Gsc-null cells. Furthermore, the nasal capsules and mandibles of the chimeras had defects similar to Gsc-null mice that varied in severity depending upon the proportion of Gsc-null cells. These results combined with the analysis of Gsc-null mice suggest that Gsc functions cell autonomously in mesenchyme-derived tissues of the head. A developmental analysis of the tympanic ring bone, a bone that is always absent in Gsc-null mice because of defects at the cell condensation stage, showed that Gsc-null cells had the capacity to form the tympanic ring condensation in the presence of wild-type cells. However, analysis of the tympanic ring bones of 18.5 d.p.c. chimeras suggests that Gsc-null cells were not maintained. The participation of Gsc-null cells in the tympanic ring condensation of chimeras may be an epigenetic phenomenon that results in a local environment in which more precursor cells are present. Thus, the skeletal defects observed in Gsc-null mice may reflect a regional reduction of precursor cells during embryonic development.


Association Between Melanoma Detected During Routine Skin Checks and Mortality.
Early melanoma diagnosis is associated with better health outcomes, but there is insufficient evidence that screening, such as having routine skin checks, reduces mortality. To assess melanoma-specific and all-cause mortality associated with melanomas detected through routine skin checks, incidentally or patient detected. A secondary aim was to examine patient, sociodemographic, and clinicopathologic factors associated with different modes of melanoma detection. This prospective, population-based, cohort study included patients in New South Wales, Australia, who were diagnosed with melanoma over 1 year from October 23, 2006, to October 22, 2007, in the Melanoma Patterns of Care Study and followed up until 2018 (mean [SD] length of follow-up, 11.9 [0.3] years) by using linked mortality and cancer registry data. All patients who had invasive melanomas recorded at the cancer registry were eligible for the study, but the number of in situ melanomas was capped. The treating doctors recorded details of melanoma detection and patient and clinical characteristics in a baseline questionnaire. Histopathologic variables were obtained from pathology reports. Of 3932 recorded melanomas, data were available and analyzed for 2452 (62%; 1 per patient) with primary in situ (n = 291) or invasive (n = 2161) cutaneous melanoma. Data were analyzed from March 2020 to January 2021. Melanoma-specific mortality and all-cause mortality. A total of 2452 patients were included in the analyses. The median age at diagnosis was 65 years (range, 16-98 years), and 1502 patients (61%) were men. A total of 858 patients (35%) had their melanoma detected during a routine skin check, 1148 (47%) self-detected their melanoma, 293 (12%) had their melanoma discovered incidentally when checking another skin lesion, and 153 (6%) reported "other" presentation. Routine skin-check detection of invasive melanomas was associated with 59% lower melanoma-specific mortality (subhazard ratio, 0.41; 95% CI, 0.28-0.60; P < .001) and 36% lower all-cause mortality (hazard ratio, 0.64; 95% CI, 0.54-0.76; P < .001), adjusted for age and sex, compared with patient-detected melanomas. After adjusting for prognostic factors including ulceration and mitotic rate, the associations were 0.68 (95% CI, 0.44-1.03; P = .13), and 0.75 (95% CI, 0.63-0.90; P = .006), respectively. Factors associated with higher odds of routine skin-check melanoma detection included being male (female vs male, odds ratio [OR], 0.73; 95% CI, 0.60-0.89; P = .003), having previous melanoma (vs none, OR, 2.36; 95% CI, 1.77-3.15; P < .001), having many moles (vs not, OR, 1.39; 95% CI, 1.10-1.77; P = .02), being 50 years or older (eg, 50-59 years vs <40 years, OR, 2.89; 95% CI, 1.92-4.34; P < .001), and living in nonremote areas (eg, remote or very remote vs major cities, OR, 0.23; 95% CI, 0.05-1.04; P = .003). In this cohort study, melanomas diagnosed through routine skin checks were associated with significantly lower all-cause mortality, but not melanoma-specific mortality, after adjustment for patient, sociodemographic, and clinicopathologic factors.


G-quadruplex structures in the human genome as novel therapeutic targets.
G-quadruplexes are secondary structures that may form within guanine-rich nucleic acid sequences. Telomeres have received much attention in this regard since they can fold into several distinct intramolecular G-quadruplexes, leading to the rational design and development of G-quadruplex‑stabilizing molecules. These ligands were shown to selectively exert an antiproliferative and chemosensitizing activity in in vitro and in vivo tumor models, without appreciably affecting normal cells. Such findings point to them as possible drug candidates for clinical applications. Other than in telomeres, G-quadruplexes may form at additional locations in the human genome, including gene promoters and untranslated regions. For instance, stabilization of G-quadruplex structures within the promoter of MYC, KIT, or KRAS resulted in the down-regulation of the corresponding oncogene either in gene reporter assays or in selected experimental models. In addition, the alternative splicing of a number of genes may be affected for a therapeutic benefit through the stabilization of G-quadruplexes located within pre-mRNAs. It is now emerging that G-quadruplex structures may act as key regulators of several biological processes. Consequently, they are considered as attractive targets for broad-spectrum anticancer therapies, and much effort is being made to develop a variety of ligands with improved G-quadruplex recognition properties. Quarfloxin, a fluoroquinolone derivative designed to target a G-quadruplex within ribosomal DNA and disrupt protein-DNA interactions, has entered clinical trials for different malignancies. This review will provide some hints on the role of G-quadruplex structures in biological processes and will evaluate their implications as novel therapeutic targets.


Effect of habituation to tea tree (Melaleuca alternifolia) oil on the subsequent susceptibility of Staphylococcus spp. to antimicrobials, triclosan, tea tree oil, terpinen-4-ol and carvacrol.
The aim of this study was to seek additional data on the antimicrobial susceptibility of Staphylococcus spp. after habituation to low levels of the topical antimicrobial agent tea tree (Melaleuca alternifolia) oil. Meticillin-susceptible Staphylococcus aureus (MSSA), meticillin-resistant S. aureus (MRSA) and coagulase-negative staphylococci (CoNS) were habituated to 0.075% tea tree oil for 3 days. Subsequently, the susceptibility of five isolates each of MSSA, MRSA and CoNS to fusidic acid, mupirocin, chloramphenicol, linezolid and vancomycin was determined by Etest, and susceptibility to tea tree oil, terpinen-4-ol, carvacrol and triclosan was determined by agar dilution. Following habituation to 0.075% tea tree oil, antimicrobial MICs differed between control and habituated isolates on 33 occasions (out of a possible 150), with MICs being higher in habituated isolates on 22 occasions. Using clinical breakpoint criteria, one MSSA isolate changed susceptibility category from vancomycin-susceptible (MIC=2 μg/mL) to intermediate susceptibility (MIC=3 μg/mL) after habituation in one of two replicates. For the non-antibiotic antimicrobial agents, MICs of habituated and control isolates differed on 12 occasions (out of a possible 120); 10 occasions in MRSA and 2 occasions in MSSA. MICs were higher for habituated isolates on five occasions. However, all the differences were one serial dilution only and were not regarded as significant. Habituation to sublethal concentrations of tea tree oil led to minor changes in MICs of antimicrobial agents, only one of which may have been clinically relevant. There is no evidence to suggest that tea tree oil induces resistance to antimicrobial agents.


Manometric evaluation of defecation disorders: Part II. Fecal incontinence.
Fecal incontinence is a silent affliction that often leads to self-imposed ostracism. For many years, a lack of understanding regarding its pathophysiology and a lack of empathy among many physicians has bedeviled this problem. However, during the last two decades, remarkable strides have been made, both in the evaluation and in the treatment of incontinence. These advances stem from the ability to perform a detailed and comprehensive assessment of anorectal physiology. Anorectal manometry has spearheaded this renaissance. Manometry is not a single test but consists of a series of measurements that include an assessment of anal sphincter function, rectal sensation, rectoanal reflexes, and rectal compliance. Electrophysiological assessments such as pudendal nerve terminal latency can provide additional information regarding neuromuscular integrity. Newer techniques such as vectography, saline continence test, impedance planimetry, and prolonged ambulatory anorectal manometry have added a new dimension to the overall assessment. Radiological tests such as defecography and anal endosonography can provide complimentary information. These tests of anorectal function have advanced immensely our understanding of the pathophysiological mechanisms that are responsible for fecal incontinence. Equipped with sound objective information, today, it is possible to treat most incontinent patients with novel treatments that include medical, biofeedback, or surgical therapies. This is the second article in a two-part evaluation of defecation disorders that discusses the manometric evaluation of fecal incontinence.


Sugar-Sweetened and Diet Beverage Consumption in Philadelphia One Year after the Beverage Tax.
In January 2017, Philadelphia (Pennsylvania) implemented an excise tax ($ 0.015/ounce) on sugar-sweetened and diet beverages. This study is a general population-based study to report on the longer-term impacts of the tax on within-person changes in consumption 12 months after implementation. A quasi-experimental difference-in-difference design was used to contrast Philadelphia vs. nearby comparison cities (Trenton, New Jersey; Camden, New Jersey; and Wilmington, Delaware) at baseline (December 2016-January 2017) vs. 12-month follow-up (December 2017-February 2018). A random-digit-dialing phone survey was administered to a population-based cohort. Analyses assessed changes in 30-day consumption frequency and ounces of sugar-sweetened and diet beverages (and a substitution beverage, bottled water) in the analytic sample (N = 515). After 12 months, relative to the comparison group, Philadelphians were slightly more likely to decrease their frequency of sugar-sweetened beverage consumption (39.2% vs. 33.5%), and slightly less likely to increase their frequency of sugar-sweetened beverage consumption (38.9% vs. 43.0%). The effects of the tax estimated in the adjusted difference-in-difference analysis were very small (for example, changes in monthly sugar-sweetened beverage consumption in Philadelphia relative to comparison cities was -3.03 times or -51.65 ounces) and confidence intervals were very wide. Results suggested that, one year after implementation, there was no major overall impact of the tax on general population-level consumption of sugar-sweetened or diet beverages, or bottled water. Future studies should test whether the tax's effect differs in vulnerable sub-populations.


An overview of home health aides: United States, 2007.
This report presents national estimates of home health aides providing assistance in activities of daily living (ADLs) and employed by agencies providing home health and hospice care in 2007. Data are presented on demographics, training, work environment, pay and benefits, use of public benefits, and injuries. Estimates are based on data collected in the 2007 National Home Health Aide Survey. Estimates are derived from data collected during telephone interviews with home health aides providing assistance with ADLs and employed by agencies providing home health and hospice care. In the United States in 2007, 160,700 home health and hospice aides provided ADL assistance and were employed by agencies providing home health and hospice care. Most home health aides were female; approximately one-half were white and one-third black. Approximately one-half of aides were at least 35 years old. Two-thirds had an annual family income of less than $40,000. More than 80% received initial training to become a home health aide and more than 90% received continuing education classes in the previous 2 years. Almost three-quarters of aides would definitely become a home health aide again, and slightly more than one-half of aides would definitely take their current job again. The average hourly pay was $10.88 per hour. Almost three-quarters of aides reported that they were offered health insurance by their employers, but almost 19% of aides had no health insurance coverage from any source. More than 1 in 10 aides had had at least one work-related injury in the previous 12 months. The picture that emerges from this analysis is of a financially vulnerable workforce, but one in which the majority of aides are satisfied with their jobs. The findings may be useful in informing initiatives to train, recruit, and retain these direct care workers.


Increased platelet aggregate formation in patients with chronic airflow obstruction and hypoxaemia.
Platelet aggregate formation in vivo was assessed by means of the platelet aggregate ratio and from platelet release products (beta thromboglobulin, platelet factor 4, thromboxane B2) in 23 patients with chronic airflow obstruction with and without hypoxaemia and in 10 control subjects without respiratory disease. Eight of the 11 hypoxaemic patients were having long term oxygen therapy. The platelet aggregate ratio was lower in the hypoxaemic patients (0.88 (SE 0.03] than in the non-hypoxaemic (0.97 (0.01] and control groups (1.00 (0.02], and there was a trend to lower aggregate ratios in the more hypoxaemic patients. Platelet release products in the peripheral venous blood were not increased in the patients or control subjects. Platelet behaviour is altered in chronic hypoxaemia and this enhanced platelet activity could contribute to the pulmonary vascular damage found in these patients through direct effects or mediator release.


Delta-aminolevulinic acid dehydratase genotype and lead toxicity: a HuGE review.
The ALAD gene (chromosome 9q34) codes for delta-aminolevulinic acid dehydratase (ALAD) (E.C. 18.104.22.168). ALAD catalyzes the second step of heme synthesis and is polymorphic. The ALAD G177C polymorphism yields two codominant alleles, ALAD-1 and ALAD-2, and it has been implicated in susceptibility to lead toxicity. Genotype frequencies vary by geography and race. The rarer ALAD-2 allele has been associated with high blood lead levels and has been thought to increase the risk of lead toxicity by generating a protein that binds lead more tightly than the ALAD-1 protein. Other evidence suggests that ALAD-2 may confer resistance to the harmful effects of lead by sequestering lead, making it unavailable for pathophysiologic participation. Recent studies have shown that individuals who are homozygous for the ALAD-1 allele have higher cortical bone lead levels; this implies that they may have a greater body lead burden and may be at higher risk of the long-term effects of lead. Individuals exposed to lead in occupational settings have been the most frequent subjects of study. Genotype selection bias may limit inferences from these studies. No firm evidence exists for an association between ALAD genotype and susceptibility to lead toxicity at background exposure levels; therefore, population testing for the ALAD polymorphism is not justified.


Beyond the use of modifiers in selective alkyne hydrogenation: silver and gold nanocatalysts in flow mode for sustainable alkene production.
We report on the excellent stereo and chemoselectivity of nanosized silver and gold catalysts in the three-phase hydrogenation of acetylenic compounds under flow chemistry conditions. The materials featuring metal nanoparticles in the range of 2-21 nm were prepared by spray deposition or incipient wetness impregnation of silver nitrate and sol immobilisation of gold chloride on different carriers (Al2O3, SiO2, TiO2, and carbon), followed by activation in various atmospheres. The samples were characterised by ICP-OES, N2 sorption, XPS, HAADF-STEM, and HRTEM, and evaluated in a continuous-flow flooded-bed micro-reactor. Both metals display optimal activities for particles below 5 nm, enabling stable operation at T = 373 K and P = 10 bar. While the performance of the silver catalysts is less influenced by the support, the gold nanoparticles exhibit significant activity only when deposited on TiO2, likely due to the strong metal-support interaction. Hydrogenations of functionalised alkynes reveal that silver and gold match, and in some cases exceed, the selectivity of benchmark palladium-based catalysts. Furthermore, in contrast to Pd, the Ag and Au samples require no modifiers, which brings fundamental and practical simplifications for their understanding and large scale manufacture. Therefore, these materials could be advantageously used for the continuous production of olefinic intermediates in the fine chemical and pharmaceutical industries.


Cigarette smoking and bone mineral density in the elderly.
To test the hypothesis that cigarette smoking is associated with reduced bone mineral density in elderly men and women. Cross sectional study. These comprised 224 men and 186 women aged 61-73 years, born and resident in East Hertfordshire. Lumbar spine and femoral neck bone mineral density (BMD) were determined by dual energy x ray absorptiometry. After adjusting for potential confounding variables, men who were current smokers were found to have a lumbar spine BMD that was 7.3% (95% CI 0.4, 14.2) lower than men who had never smoked. Similarly, women who were current smokers had a BMD value that was 7.7% (95% CI 0.3, 15.6) lower than in women who had never smoked. The difference at the femoral neck was smaller and not statistically significant. For both men and women, each decade of smoking was associated with a reduction of 0.015 g/cm2 in BMD at the lumbar spine (95% CI: men 0.002, 0.027; women 0.003, 0.028). At the femoral neck the reduction in BMD was 0.011 g/cm2 (95% CI 0.003, 0.020) for men and 0.004 g/cm2 (95% CI -0.003, 0.012) for women with each decade of smoking. The results show an adverse effect of smoking on BMD which was most noticeable at the lumbar spine, and seemed stronger in men than women. This effect could not be explained by differences in life style between smokers and nonsmokers.


Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas.
Pre-existing and acquired drug resistance are major obstacles to the successful treatment of glioblastomas. We used an integrated resistance model and genomics tools to globally explore molecular factors and cellular pathways mediating resistance to O6-alkylating agents in glioblastoma cells. We identified a transcriptomic signature that predicts a common in vitro and in vivo resistance phenotype to these agents, a proportion of which is imprinted recurrently by gene dosage changes in the resistant glioblastoma genome. This signature was highly enriched for genes with functions in cell death, compromise, and survival. Modularity was a predominant organizational principle of the signature, with functions being carried out by groups of interacting molecules in overlapping networks. A highly significant network was built around nuclear factor-kappaB (NF-kappaB), which included the persistent alterations of various NF-kappaB pathway elements. Tumor necrosis factor-alpha-induced protein 3 (TNFAIP3) was identified as a new regulatory component of a putative cytoplasmic signaling cascade that mediates NF-kappaB activation in response to DNA damage caused by O6-alkylating agents. Expression of the corresponding zinc finger protein A20 closely mirrored the expression of the TNFAIP3 transcript, and was inversely related to NF-kappaB activation status in the resistant cells. A prediction model based on the resistance signature enabled the subclassification of an independent, validation cohort of 31 glioblastomas into two outcome groups (P = .037) and revealed TNFAIP3 as part of an optimized four-gene predictor associated significantly with patient survival (P = .022). Our results offer strong evidence for TNFAIP3 as a key regulator of the cytoplasmic signaling to activate NF-kappaB en route to O6-alkylating agent resistance in glioblastoma cells. This pathway may be an attractive target for therapeutic modulation of glioblastomas.


Fungal myocarditis.
The incidence of invasive fungal disease has dramatically increased over the past few decades corresponding to the rising number of immunocompromised patients. The major risk factors for severe fungal disease include administration of broad-spectrum antibiotics, corticosteroids and cytotoxic agents, invasive medical procedures, and Human Immunodeficiency Virus (HIV) infection. Invasive fungal infections often affect multiple organs, and involvement of the myocardium frequently occurs in disseminated disease. Premortem diagnosis of fungal myocarditis is difficult since clinical findings of myocardial involvement are often absent or ambiguous and blood cultures are often negative. The major fungal pathogens responsible for myocardial infection and the clinical settings in which they occur are reviewed.


Intestinal Virome Signature Associated With Severity of Nonalcoholic Fatty Liver Disease.
Alterations in the gut microbiome have been associated with the severity of nonalcoholic fatty liver disease (NAFLD). Previous studies focused exclusively on the bacteria in the microbiome; we investigated changes in the viral microbiome (virome) in patients with NAFLD. In a prospective, cross-sectional, observational study, we extracted RNA and DNA virus-like particles from fecal samples from 73 patients with NAFLD: 29 patients had an NAFLD Activity Score (NAS) of 0-4, 44 patients had an NAS of 5-8 or liver cirrhosis (LCI), 37 patients had F0-F1 fibrosis, and 36 patients had F2-F4 fibrosis. As controls, 9 individuals without liver disease and 13 patients with mild primary biliary cholangitis were included in the analysis. We performed shotgun metagenomic sequencing of virus-like particles. Patients with NAFLD and NAS 5-8/LCI had a significant decrease in intestinal viral diversity compared with patients with NAFLD and NAS 0-4 or control individuals. The presence of more advanced NAFLD was associated with a significant reduction in the proportion of bacteriophages compared with other intestinal viruses. Using multivariate logistic regression analysis with leave-1-out cross validation, we developed a model, including a viral diversity index and simple clinical variables, that identified patients with NAS 5-8/LCI with an area under the curve of 0.95 (95% confidence interval, 0.91-0.99) and F2-F4 fibrosis with an area under the curve of 0.88 (95% confidence interval, 0.80-0.95). Addition of data on viral diversity significantly improved multivariate models, including those based on only clinical parameters or bacterial diversity. In a study of fecal viromes from patients with NAFLD and control individuals, we associated histologic markers of NAFLD severity with significant decreases in viral diversity and proportion of bacteriophages. We developed a model based on fecal viral diversity and clinical data that identifies patients with severe NAFLD and fibrosis more accurately than models based only on clinical or bacterial data.


Impacts of Acidification and Potential Recovery on the Expected Value of Recreational Fisheries in Adirondack Lakes (USA).
We estimated the potential economic value of recreational fisheries in lakes altered by acid pollution in the Adirondack Mountains (USA). We found that the expected value of recreational fisheries has been diminished because of acid deposition but may improve as lakes recover from acidification under low emissions scenarios combined with fish stocking. Fishery value increased with lake pH, from a low of $4.41 angler day-1 in lakes with pH < 4.5, to a high of $38.40 angler day-1 in lakes with pH > 6.5 that were stocked with trout species. Stocking increased the expected fishery value by an average of $11.50 angler day-1 across the entire pH range of the lakes studied. Simulating the future long-term trajectory of a subset of lakes, we found that pH and expected fishery value increased over time in all future emissions scenarios. Differences in estimated value among pollution reduction scenarios were small (<$1 angler day-1) compared to fish stocking scenarios (>$4 angler day-1). Our work provides a basis for assessing the costs and benefits of emissions reductions and management efforts that can hasten recovery of the economic and cultural benefits of ecosystems degraded by chronic pollution.


Complications following cervical epidural steroid injections by expert interventionalists in 2003.
Two major portals are available for delivery of medication into the cervical epidural space: interlaminar and transforaminal. The choice of which approach to use is commonly made by assessing the patient's structural pathology, one's skill in performing each procedure, and then weighing the advantages versus the risk associated with the particular technique. Over the past several years, a growing number of cases involving serious complications following cervical transforaminal epidural steroid injections have led some to question the safety of the procedure and to preferentially perform interlaminar epidural injections. To explore the prevalence of complications caused by transforaminal versus interlaminar injections. Retrospective survey. We selected the list of course instructors of the International Spine Intervention Society (ISIS) as our source for expert spine injection specialists. All data were collected by survey during a period from April 2004 through June 2004. Questions were asked about the type of cervical epidural injections performed and any complications during the preceding 12 months, January through December 2003. All 29 ISIS course instructors were surveyed. Seventeen instructors replied. In 2003, an estimated total of 5968 cervical epidural injections were performed by 17 instructors for neck and/or arm pain. The interlaminar approach was performed in 4389 cases by 14 instructors and the transforaminal approach was used in 1579 cases by 16 of the instructors. Of the 4389 interlaminar injections there were 23 cases (0.52%) of various minor complications including headaches caused by dural puncture, transient vagal episodes, and prolonged complaints of new or increased numbness and paresthesias. In the 1579 transforaminal there were five cases (0.32%) of minor complications including aggravated radicular pain, prolonged paresthesias, and skin rashes. In addition, 2 cases of radicular artery injection were confirmed by digital subtraction angiography during 354 transforaminal approaches performed by one physician. The rates of complication were not different between interlaminar and transforaminal approaches. When performed by experienced interventionalists, major complications are probably rare and it could take years for a significant complication to occur. We must however all be aware that these complications can occur.


Robust heart rate estimation using wrist-type photoplethysmographic signals during physical exercise: an approach based on adaptive filtering.
Photoplethysmographic (PPG) signals are easily corrupted by motion artifacts when the subjects perform physical exercise. This paper introduces a two-step processing scheme to estimate heart rate (HR) from wrist-type PPG signals strongly corrupted by motion artifacts. Adaptive noise cancellation, using normalized least-mean-square algorithm, is first performed to attenuate motion artifacts and reconstruct multiple PPG waveforms from different combinations of corrupted PPG waveforms and accelerometer data. An adaptive band-pass filter is then used to track the common instantaneous frequency component (i.e. HR) of the reconstructed PPG waveforms. The proposed HR estimation scheme was evaluated on two datasets, composed of records from running subjects and subjects performing different kinds of arm/forearm movements and resulted in average absolute errors of 1.40 ± 0.60 and 4.28 ± 3.16 beats-per-minute for these two datasets, respectively. Importantly, the proposed method is fully automatic, induces an average estimation delay of 0.93 s, and is therefore suitable for real-time monitoring applications.


Colonization with multidrug-resistant organisms is associated with in increased mortality in liver transplant candidates.
Rising prevalence of multidrug-resistant organisms (MDRO) is a major health problem in patients with liver cirrhosis. The impact of MDRO colonization in liver transplantation (LT) candidates and recipients on mortality has not been determined in detail. Patients consecutively evaluated and listed for LT in a tertiary German liver transplant center from 2008 to 2018 underwent screening for MDRO colonization including methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant gram-negative bacteria (MDRGN), and vancomycin-resistant enterococci (VRE). MDRO colonization and infection status were obtained at LT evaluation, planned and unplanned hospitalization, three months upon graft allocation, or at last follow-up on the waiting list. In total, 351 patients were listed for LT, of whom 164 (47%) underwent LT after a median of 249 (range 0-1662) days. Incidence of MDRO colonization increased during waiting time for LT, and MRDO colonization was associated with increased mortality on the waiting list (HR = 2.57, p<0.0001. One patients was colonized with a carbapenem-resistant strain at listing, 9 patients acquired carbapenem-resistant gram-negative bacteria (CRGN) on the waiting list, and 4 more after LT. In total, 10 of these 14 patients died. Colonization with MDRO is associated with increased mortality on the waiting list, but not in short-term follow-up after LT. Moreover, colonization with CRGN seems associated with high mortality in liver transplant candidates and recipients.


Dental occlusion: modern concepts and their application in implant prosthodontics.
The aim of this article was to review the literature on various aspects of occlusion related to implant prosthodontics, using PubMed and the Cochrane library. Even if the number of studies on implants and prosthodontics is very large, no randomized controlled trials or Cochrane reviews were found on the possible influence of occlusal design or characteristics of occlusion on treatment outcome. Therefore, studies and articles of a lower evidence level were accepted as the main part of the review. The widely spread opinion that implants are superior to natural teeth was refuted by two recent consensus conferences, which concluded that the long-term outcome of implant restorations is not better than that of natural teeth. No controlled studies on the optimal features of a harmonious natural and/or restored occlusion, including implant prostheses, were found. Nor was there any evidence that more sophisticated methods in jaw registration, e.g., using face-bows and adjustable articulators, compared with simpler methods, will yield better clinical prosthodontic results. This article discusses, among other things, concepts of occlusion of implant-supported restorations, occlusal material, cantilevers, and occlusal risk factors. Within the limitations of the review, it was concluded that many factors can influence implant failure and peri-implant bone loss but that little is known of the relative importance of such factors. Most probably, however, occlusal factors and details of occlusion are in general of minor importance for the outcome of implant restorations. Occlusion can be managed successfully by using simple methods for jaw registration and different occlusal concepts.


Biopsychosocial rehabilitation for repetitive-strain injuries among working-age adults.
The objective of this study was to determine the effectiveness of biopsychosocial rehabilitation for upper-limb repetitive-strain injuries among working-age adults. Studies were identified from electronic bibliographic databases, reference checks, and consultations with experts in rehabilitation. Four blinded reviewers selected randomized controlled and controlled trials. Two experts evaluated the clinical relevance of the findings. Two other reviewers extracted the data and assessed the main results and the methodological quality of the studies. Finally, a qualitative analysis was performed. Only 2 studies satisfied the criteria. They were both considered to be low-quality trials. The clinical relevance of the included studies was also unsatisfactory. The level of scientific evidence was limited, showing that hypnosis as a supplement to comprehensive treatment can decrease the pain intensity of acute repetitive-strain injury in short follow-ups. There appears to be little scientific evidence for the effectiveness of biopsychosocial rehabilitation with respect to repetitive-strain injuries.


Enzymetically regulating the self-healing of protein hydrogels with high healing efficiency.
Enzyme-mediated self-healing of dynamic covalent bond-driven protein hydrogels was realized by the synergy of two enzymes, glucose oxidase (GOX) and catalase (CAT). The reversible covalent attachment of glutaraldehyde to lysine residues of GOX, CAT, and bovine serum albumin (BSA) led to the formation and functionalization of the self-healing protein hydrogel system. The enzyme-mediated protein hydrogels exhibit excellent self-healing properties with 100% recovery. The self-healing process was reversible and effective with an external glucose stimulus at room temperature.


The islet amyloid polypeptide gene and non-insulin-dependent diabetes mellitus in south Indians.
Islet amyloid polypeptide (IAPP), otherwise called amylin, is the monomeric component of islet amyloid. Deposition of this amyloid is a characteristic feature of non-insulin-dependent diabetes mellitus in humans and may play a role in the pathogenesis of the disease. As such, abnormalities in the structure or expression of the IAPP gene might contribute to the inheritance of this condition. The IAPP gene was studied in a well-characterised population of 62 unrelated Dravidian subjects with non-insulin-dependent diabetes mellitus and 56 normal Dravidian controls, using a restriction fragment length polymorphism generated by PvuII digestion. Genotype and allele frequencies did not differ between diabetic subjects and controls. Taken together with recent findings in Europid and other racial groups, an abnormality of the IAPP gene is highly unlikely to represent a major gene for the development of non-insulin-dependent diabetes mellitus.


Prices and cross-border cigarette purchases in the EU: evidence from demand modelling.
Previous studies of cross-border cigarette purchases in the European Union (EU) relied on survey-reported data. Results of those studies might be affected by under-reporting of tax avoidance in those surveys. This study aims to shed light on the effects of cigarette price differences between EU Member States on cross-border cigarette purchases using a method that is free from potential reporting bias. 2004-2017 pooled time-series data and econometric modelling are used to examine cross-border shopping in the EU. Incentives for cross-border shopping are measured as a function of differences in cigarette prices between bordering countries, controlling for population density near borders. Separate incentive variables are calculated for EU internal versus EU external borders and for terrestrial versus maritime borders. Tax-paid cigarette sales are modelled as a function of cigarette price, per capita income, non-price measures and the incentive variables using fixed-effects models. The estimated price elasticity of cigarette demand varies, depending on the model, from -0.47 to -0.35. The estimated income elasticity varies from 0.66 to 0.70. Between-country price differences are not significantly associated with purchases across maritime borders and across borders with non-EU neighbours. In an average EU Member State, reducing incentives from cross-border shopping down to zero would increase sales by 1.5% in an importing country and reduce sales by about 6% in an exporting country, ceteris paribus. An upward convergence of cigarette prices across EU Member States would reduce cross-border cigarette purchasing and improve public health by contributing to decreases in cigarette consumption.


Fatty acids, essential oil and phenolics composition of Silybum marianum seeds and their antioxidant activities.
The presentstudydescribes the biochemical evaluation of Silybum marianum seed. The analysis of essential oil composition of Silybum marianum seed by Gas Chromatography-Mass Spectrometry GC-MS showed the presence of14 volatile components with the predominance of γ-cadinene (49.8%) and α-pinene (24.5%). Whereas, the analysis of fatty acids composition, showed the predominance of linoleic (50.5%) and oleic (30.2%) acids. Silybum marainum presented also an important polyphenol contents with 29mgGAE/g DW, a good antiradical activity (CI(50)=39μg/ml) but a lower reducing power ability. Flavonoid and condensed tannin contents were about 3.39mg EC/g DW and 1.8mg EC/gDW, respectively. The main phenolic compounds identified by RP-HPLC, were silybin A (12.2%), silybin B (17.67%), isosilybin A (21.9%), isosilybin B (12.8%), silychristin (7.9%) andsilydianin (7.5%).


Reduced blood brain barrier breakdown in P-selectin deficient mice following transient ischemic stroke: a future therapeutic target for treatment of stroke.
The link between early blood- brain barrier (BBB) breakdown and endothelial cell activation in acute stroke remain poorly defined. We hypothesized that P-selectin, a mediator of the early phase of leukocyte recruitment in acute ischemia is also a major contributor to early BBB dysfunction following stroke. This was investigated by examining the relationship between BBB alterations following transient ischemic stroke and expression of cellular adhesion molecule P-selectin using a combination of magnetic resonance molecular imaging (MRMI), intravital microscopy and immunohistochemistry. MRMI was performed using the contrast, gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) conjugated to Sialyl Lewis X (Slex) where the latter is known to bind to activated endothelium via E- or P selectins. Middle cerebral artery occlusion was induced in male C57/BL 6 wild-type (WT) mice and P-selectin-knockout (KO) mice. At 24 hours following middle cerebral artery occlusion, T1 maps were acquired prior to and following contrast injection. In addition to measuring P- and E-selectin expression in brain homogenates, alterations in BBB function were determined immunohistochemically by assessing the extravasation of immunoglobulin G (IgG) or staining for polymorphonuclear (PMN) leukocytes. In vivo assessment of BBB dysfunction was also investigated optically using intravital microscopy of the pial circulation following the injection of Fluorescein Isothiocyanate (FITC)-dextran (MW 2000 kDa). MRI confirmed similar infarct sizes and T1 values at 24 hours following stroke for both WT and KO animals. However, the blood to brain transfer constant for Gd DTPA (Kgd) demonstrated greater tissue extravasation of Gd DTPA in WT animals than KO mice (P < 0.03). In the P selectin KO mice, Delta T1 stroke -Delta T1 contralateral control cortex, decreased significantly in the Gd-DTPA(sLeX) group compared to Gd-DTPA, indicative of sLeX mediated accumulation of the targeted contrast agent. Regarding BBB function, in the P-selectin KO mice compared to WT control mice, there was an attenuation in the extravasation of IgG (P < 0.001), a trend for decreased FITC extravasation and less infiltration of PMN leukocytes (P < 0.001) thereby supporting the observed increase in Kgd permeability in stroke brain of WT compared to KO mice. P-selectin expression contributes to enhanced BBB dysfunction at 24 hours after transient focal cerebral ischemia.


Complications following Staged Hypospadias Repair Using Transposed Preputial Skin Flaps.
Proximal hypospadias repair using a staged approach is a complex reconstructive operation with the potential for significant complications requiring repeat surgery. We report outcomes of staged hypospadias repair using transposed preputial skin flaps and factors predictive of postoperative complications. We retrospectively analyzed patients who underwent staged proximal hypospadias repair using transposed preputial skin flaps between 2002 and 2013. Patient demographics, operative details, complications, reoperations and factors predictive of complications were reviewed. A total of 56 patients were identified with a mean age of 14.1 months (median 14.3) at first stage. Mean followup was 38.6 months (median 34.1). Complications requiring additional unplanned operation(s) were observed in 38 patients (68%), including fistulas in 32 (57%), diverticula in 8 (14%), meatal stenosis in 5 (9%), urethral stricture in 8 (14%) and glans dehiscence in 3 (5%). In addition, redo first stage repair was performed in 4 patients (7%). Since some patients had more than 1 complication, the total number of complications is greater than the number of patients undergoing a redo operation. On univariate analyses the use of small intestinal submucosa was significantly associated with an increased risk of fistula (91% vs 49%, p = 0.02) and urethral diverticulum (64% vs 24%, p = 0.04). Incision of the tunica albuginea of the corpora was associated with an increased likelihood of fistula (77% vs 44%, p = 0.03). Finally, patients with glans dehiscence were significantly younger at first stage (5.8 vs 14.8 months, p = 0.01). The reoperation rate for complications in children undergoing staged hypospadias repair using transposed preputial skin flaps is higher than previously reported.


Masked megaloblastic anemia.
In six patients, eight episodes of anemia associated with folic acid or vitamin B12 deficiency were unaccompanied by macrocytosis. Six of the eight episodes of anemia were complicated by illnesses of an inflammatory or infectious nature, two patients had iron deficiency, two appeared to have a thalassemia trait, and one had severe renal failure. In five of the eight episodes, erythropoiesis was not megaloblastic and there was insufficient anisocytosis or poikilocytosis to suggest an underlying vitamin deficiency state. Hypersegmented neutrophils were observed in all episodes, but a neutrophil lobe average of greater than 3.5 lobes per cell was observed only once, and in one patient, less than 5% of the circulating neutrophils were hypersegmented. Giant metamyelocytes, however, were present in the marrow in all of the episodes and provided an important clue to the presence of the vitamin deficiency state.


Ultra-high-frequency ultrasound and machine learning approaches for the differential diagnosis of melanocytic lesions.
Malignant melanoma (MM) is one of the most dangerous skin cancers. The aim of this study was to present a potential new method for the differential diagnosis of MM from melanocytic naevi (MN). We examined 20 MM and 19 MN with a new ultra-high-frequency ultrasound (UHFUS) equipped with a 70 MHz linear probe. Ultrasonographic images were processed for calculating 8 morphological parameters (area, perimeter, circularity, area ratio, standard deviation of normalized radial range, roughness index, overlap ratio and normalized residual mean square value) and 122 texture parameters. Colour Doppler images were used to evaluate the vascularization. Features reduction was implemented by means of principal component analysis (PCA), and 23 classification algorithms were tested on the reduced features using histological response as ground-truth. Best results were obtained using only the first component of the PCA and the weighted k-nearest neighbour classifier; this combination led to an accuracy of 76.9%, area under the ROC curve of 83%, sensitivity of 84% and specificity of 70%. The histological analysis still remains the gold-standard, but the UHFUS images processing using a machine learning approach could represent a new non-invasive approach.


"Ask Ernö": a self-learning tool for assignment and prediction of nuclear magnetic resonance spectra.
We present "Ask Ernö", a self-learning system for the automatic analysis of NMR spectra, consisting of integrated chemical shift assignment and prediction tools. The output of the automatic assignment component initializes and improves a database of assigned protons that is used by the chemical shift predictor. In turn, the predictions provided by the latter facilitate improvement of the assignment process. Iteration on these steps allows Ask Ernö to improve its ability to assign and predict spectra without any prior knowledge or assistance from human experts. This concept was tested by training such a system with a dataset of 2341 molecules and their (1)H-NMR spectra, and evaluating the accuracy of chemical shift predictions on a test set of 298 partially assigned molecules (2007 assigned protons). After 10 iterations, Ask Ernö was able to decrease its prediction error by 17 %, reaching an average error of 0.265 ppm. Over 60 % of the test chemical shifts were predicted within 0.2 ppm, while only 5 % still presented a prediction error of more than 1 ppm. Ask Ernö introduces an innovative approach to automatic NMR analysis that constantly learns and improves when provided with new data. Furthermore, it completely avoids the need for manually assigned spectra. This system has the potential to be turned into a fully autonomous tool able to compete with the best alternatives currently available.Graphical abstractSelf-learning loop. Any progress in the prediction (forward problem) will improve the assignment ability (reverse problem) and vice versa.


Removal of giant intraosseous meningioma followed by cranioplasty using a custom-made bioceramic implant: case report.
Intraosseous meningioma of the chordoid type is a rare clinical entity. Radical surgical removal and subsequent cranioplasty is the treatment of choice. Here, the authors report a severe case involving more than 70% of the calvarial surface area, which was removed and repaired using a prefabricated custom-made, titanium-reinforced, bioceramic implant and bone-cutting guides. Tumor removal and good esthetic outcome were achieved, along with a 17.1% increase of intracranial volume. Bioceramic implants have shown promising initial results and may represent an important new tool in the surgeon's armamentarium.


Global, Regional, and National Burden of Cardiovascular Diseases for 10 Causes, 1990 to 2015.
The burden of cardiovascular diseases (CVDs) remains unclear in many regions of the world. The GBD (Global Burden of Disease) 2015 study integrated data on disease incidence, prevalence, and mortality to produce consistent, up-to-date estimates for cardiovascular burden. CVD mortality was estimated from vital registration and verbal autopsy data. CVD prevalence was estimated using modeling software and data from health surveys, prospective cohorts, health system administrative data, and registries. Years lived with disability (YLD) were estimated by multiplying prevalence by disability weights. Years of life lost (YLL) were estimated by multiplying age-specific CVD deaths by a reference life expectancy. A sociodemographic index (SDI) was created for each location based on income per capita, educational attainment, and fertility. In 2015, there were an estimated 422.7 million cases of CVD (95% uncertainty interval: 415.53 to 427.87 million cases) and 17.92 million CVD deaths (95% uncertainty interval: 17.59 to 18.28 million CVD deaths). Declines in the age-standardized CVD death rate occurred between 1990 and 2015 in all high-income and some middle-income countries. Ischemic heart disease was the leading cause of CVD health lost globally, as well as in each world region, followed by stroke. As SDI increased beyond 0.25, the highest CVD mortality shifted from women to men. CVD mortality decreased sharply for both sexes in countries with an SDI >0.75. CVDs remain a major cause of health loss for all regions of the world. Sociodemographic change over the past 25 years has been associated with dramatic declines in CVD in regions with very high SDI, but only a gradual decrease or no change in most regions. Future updates of the GBD study can be used to guide policymakers who are focused on reducing the overall burden of noncommunicable disease and achieving specific global health targets for CVD.


Human senataxin resolves RNA/DNA hybrids formed at transcriptional pause sites to promote Xrn2-dependent termination.
We present a molecular dissection of pause site-dependent transcriptional termination for mammalian RNA polymerase II (Pol II)-transcribed genes. We show that nascent transcripts form RNA/DNA hybrid structures (R-loops) behind elongating Pol II and are especially prevalent over G-rich pause sites positioned downstream of gene poly(A) signals. Senataxin, a helicase protein associated with AOA2/ALS4 neurodegenerative disorders, acts to resolve these R-loop structures and by so doing allows access of the 5'-3' exonuclease Xrn2 at 3' cleavage poly(A) sites. This affords 3' transcript degradation and consequent Pol II termination. In effect, R-loops formed over G-rich pause sites, followed by their resolution by senataxin, are key steps in the termination process.


Increased Use of Adrenaline in the Management of Childhood Anaphylaxis Over the Last Decade.
We recently determined that allergy training programs have improved physician recognition and diagnosis of pediatric anaphylaxis in the last decade. To investigate for changes in management, in particular the appropriate use of adrenaline for the treatment of anaphylaxis in a tertiary pediatric emergency department (PED). We conducted a retrospective case note study including children aged 0 to 16 years coded and verified for anaphylaxis comparing cases in years 2003/2004 with 2012. This included standardized information on clinical presentation, demographic characteristics, vital signs, mode of transport, and management of anaphylaxis including the use of adrenaline and/or adjunct therapy. Follow-up management plans were also recorded. In 2003/2004, a total of 92 cases were coded and verified for anaphylaxis from 83,832 PED presentations compared with 159 cases from 71,822 PED presentations in 2012. A significantly higher proportion of cases were appropriately managed with adrenaline in 2012 compared with 2003/2004, when intensive training programs had not yet been introduced (P = .03). Vital signs were more frequently documented in 2012 (P < .001) than in 2003/2004, and there was significantly less administration of other medications (corticosteroids, bronchodilators, and antihistamines) (P < .05). Also, changes in discharge management occurred with an improved dispensing/prescription of adrenaline autoinjectors and more frequent follow-up arrangement with specialist allergy services (P < .001). There was a significant improvement in the management of anaphylaxis over this 10-year period. This change was observed after the introduction of intensified physician training programs in which anaphylaxis management was a key component highlighting the importance of cooperation between pediatric emergency and allergy services.


Reused Cultivation Water Accumulates Dissolved Organic Carbon and Uniquely Influences Different Marine Microalgae.
Reusing growth medium (water supplemented with nutrients) for microalgae cultivation is required for economical and environmentally sustainable production of algae bioproducts (fuels, feed, and food). However, reused medium often contains microbes and dissolved organic matter that may affect algae growth. While the accumulation of dissolved organic carbon (DOC) in reused medium has been demonstrated, it is unclear whether DOC concentrations affect algae growth or subsequent rates of algal DOC release. To address these questions, lab-scale experiments were conducted with three marine microalgae strains, Navicula sp. SFP, Staurosira sp. C323, and Chlorella sp. D046, grown in medium reused up to four times. Navicula sp. and Chlorella sp. grew similarly in reused medium as in fresh medium, while Staurosira sp. became completely inhibited in reused medium. Across the three algae, there was no broad trend between initial DOC concentration in reused medium and algae growth response. Navicula sp. released less DOC overall in reused medium than in fresh medium, but DOC release rates did not decrease proportionally with increased DOC concentrations. Net DOC accumulation was much lower than gross DOC released by Navicula sp. and Staurosira sp., indicating the majority of released DOC was degraded. Additionally, biodegradation experiments with reused media showed no further net decrease in DOC, suggesting the accumulated DOC was recalcitrant to the associated bacteria. Overall, these results suggest that taxa-specific factors may be responsible for algae growth response in reused medium, and that DOC release and accumulation are insensitive to prior cultivation rounds. Choosing an algae strain that is uninhibited by accumulated DOC is therefore critical to ensure successful water reuse in the algae industry.


Regional distribution and characterization of [3H]dextrorphan binding sites in rat brain determined by quantitative autoradiography.
The pharmacologic specificity and anatomic distribution of [3H]dextrorphan recognition sites in the rat brain was characterized by quantitative autoradiography. Equilibrium saturation analysis indicated that [3H]dextrorphan labeled a single population of high affinity binding sites. These sites are heterogeneously distributed throughout rat forebrain with the following order of binding densities: hippocampal formation > cerebral cortex > thalamic nuclei > striatum. The association rate of [3H]dextrorphan with its binding site in area stratum radiatum of CA1 is accelerated by the addition of glycine and glutamate. [3H]Dextrorphan binding is, however, relatively insensitive to glycine and glutamate under equilibrium conditions, despite extensive prewashing procedures to deplete endogenous levels of these substances. The competitive N-methyl-D-aspartate (NMDA) antagonist D(-)-2-amino-5-phosphonopentanoic acid (D-AP5) and the glycine site antagonist 7-chlorokynurenic acid completely inhibit specific [3H]dextrorphan binding. D-AP5 suppresses [3H]dextrorphan binding in a regionally distinctive manner; a population of binding sites is weakly inhibited by D-AP5 in the lateral thalamic regions, whereas D-AP5 potently inhibits [3H]dextrorphan binding in the cerebral cortex. The rank order of potencies of an array of noncompetitive antagonists to inhibit [3H]dextrorphan binding unambiguously displays the pharmacologic profile of the noncompetitive antagonist domain of the NMDA receptor-channel complex. Furthermore, the distribution of [3H]dextrorphan binding sites in slide-mounted tissue appears qualitatively similar to the distribution of NMDA receptors previously reported using NMDA-displacement of [3H]glutamate, [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imi ne (MK-801) and [3H]1-[1-(2-thienyl)cyclohexyl]-piperidine (TCP) in most brain areas examined except the cerebellum. The molecular layer of the cerebellum displays a particularly high density of [3H]dextrorphan binding sites. The regional distribution of [3H]dextrorphan binding sites in rat brain does not correspond to the reported distributions of [3H]dextromethorphan or sigma binding sites.


Cost-sensitive face recognition.
Most traditional face recognition systems attempt to achieve a low recognition error rate, implicitly assuming that the losses of all misclassifications are the same. In this paper, we argue that this is far from a reasonable setting because, in almost all application scenarios of face recognition, different kinds of mistakes will lead to different losses. For example, it would be troublesome if a door locker based on a face recognition system misclassified a family member as a stranger such that she/he was not allowed to enter the house, but it would be a much more serious disaster if a stranger was misclassified as a family member and allowed to enter the house. We propose a framework which formulates the face recognition problem as a multiclass cost-sensitive learning task, and develop two theoretically sound methods for this task. Experimental results demonstrate the effectiveness and efficiency of the proposed methods.


Effect of partial posterior vitreous detachment on retinal nerve fiber layer thickness as measured by optical coherence tomography.
To evaluate the effect of partially attached posterior vitreous detachments (pPVDs) at the optic disc on retinal nerve fiber layer (RNFL) thickness as measured by optical coherence tomography. A retrospective study was conducted using stored Stratus optical coherence tomography III scans of patients with suspected glaucoma from January 2003 to September 2006 at the Montefiore Medical Center, Bronx, New York. All scans were evaluated for vitreous attachments at the disc and were divided into control (without pPVD) and pPVD groups. The RNFL thickness was compared using the fast RNFL protocol. Patients were defined as glaucoma suspects based on clinical findings of either glaucomatous-appearing optic discs or elevated intraocular pressure. All study patients had normal Humphrey visual fields. A total of 110 eyes from 110 patients were included; 59 were in the pPVD group and 51 were controls. Partial PVD was found in 40% of the glaucoma suspects. The mean RNFL thickness of eyes with pPVD was significantly broader than that of controls (101.6 microm vs 95.6 microm, respectively; P < .001). The average RNFL thickness of each quadrant was greater in the pPVD group than in the control group, with statistically significant differences in superior and inferior quadrants (P < .001 and P = .001, respectively). More than one-third of this population of glaucoma suspects had a pPVD, indicating that this is a common phenomenon. The results suggest that RNFL thicknesses are greater in patients with pPVD than in controls. This may indicate a limitation of using RNFL thickness as a criterion for evaluating glaucomatous damage in patients with pPVD.


Health impact assessments are needed in decision making about environmental and land-use policy.
The importance to public health of environmental decisions-including those about land use, transportation, power generation, agriculture, and environmental regulation-is increasingly well documented. Yet many decision makers in fields not traditionally focused on health continue to pay little if any attention to the important health effects of their work. This article examines the emerging practice of health impact assessment and offers real-world examples of its effective implementation, including studying the impact of nearby highways-a major source of air pollution-on proposed new housing for seniors. The article argues that officials at the federal, state, and local levels should consult health experts and consider using health impact assessments when their decisions on such issues as urban planning, land use, and environmental regulation have the potential to directly affect the conditions in which people live and work.


The exceptional mitochondrial DNA system of the mussel family Mytilidae.
Species of the families Mytilidae (sea mussels) and Unionidae (fresh water mussels) contain two types of mitochondrial DNA (mtDNA), the F that behaves as the standard animal mtDNA and the M that is transmitted through the sperm and establishes itself only in the male gonad. The two molecules have, therefore, separate transmission routes, one through the female and the other through the male lineage. The system has been named doubly uniparental inheritance (DUI). Another important feature of sea mussels is that the sex ratio among offspring of a pair mating is determined by the female parent only. The mechanism of DUI remains unknown. One hypothesis that is consistent with all observations is that the standard maternal inheritance was modified in mussels via the evolution of a suppressor gene that is expressed during oogenesis and has two alleles, the inactive and the active allele. In the presence of the active allele in the mother's genotype the egg is supplied with a substance that interferes and the normal mechanism of elimination of sperm mitochondria. This will explain why half of mussels have the father's mtDNA and half do not, but would not explain why presence/absence of paternal mtDNA is linked with the male and female gender, respectively. To provide an explanation for this linkage, one would have to assume that there is a causal relationship between retention of paternal mtDNA and sex determination.