Intravitreal ranibizumab for the treatment of inflammatory choroidal neovascularization.
To evaluate the effect of individualized repeated intravitreal injections of ranibizumab (Lucentis) on visual acuity and central foveal thickness in patients with choroidal neovascular membrane (CNV) associated with various ocular inflammatory clinical entities. Our study was a retrospective, noncomparative, interventional, and observational case series. Sixteen eyes of 15 consecutive patients diagnosed with inflammatory CNV treated with repeated intravitreal injections of ranibizumab were evaluated. The underlying diagnoses were toxoplasmosis (n = 4), serpiginous choroidopathy (n = 2), punctate inner choroidopathy (n = 5), multifocal choroiditis (MFC, n = 3), and scleroderma (n = 2). All patients underwent monthly optical coherence tomography (OCT) scans and fluorescein angiography/indocyanine green angiography every 1 month after every injection and then every 3 months. Optical coherence tomography scans and fluorescein angiography were performed by the same experienced physician. Repeated intravitreal injections were performed when persistent/recurrent fluid on OCT and/or signs of active CNV on angiography were present. Changes in Early Treatment Diabetic Retinopathy Study visual acuity and central foveal thickness were statistically analyzed. The mean follow-up time was 70.4 ± 24 weeks (17.6 months; range, 44-116 weeks [11-29 months]). The mean number of injections performed was 2.3, and the mean best-corrected visual acuity improved from 55 Early Treatment Diabetic Retinopathy Study letters (logarithm of the minimum angle of resolution, 0.9 ± 0.4 [mean ± SD]) at baseline to 70.3 Early Treatment Diabetic Retinopathy Study letters (logarithm of the minimum angle of resolution, 0.6 ± 0.4) at the end of the follow-up, a statistically significant change compared with baseline (P < 0.0001). The mean letter gain was 15.3 letters, and best-corrected visual acuity improved in 14 of 16 patients (88%) and remained stable in 2 patients (12.5%) without any patient demonstrating deterioration. The mean central foveal thickness (although not excessively increased at baseline) improved from 285 ± 20 μm at baseline to 233 ± 21 μm (statistically significant compared with baseline, P < 0.0001) at the end of the follow-up. At the end of the follow-up, all patients demonstrated CNV regression, and retinal pigment epithelial atrophy surrounding the regressed CNV was developed in 11 of the 16 eyes (68.8%). During the same period, no CNV recurrence was observed and no injection-related complications such as cataract, retinal detachment, endophthalmitis, or exacerbation of uveitis were noted. Overall, our findings suggest that intravitreal injections of ranibizumab have shown promising results in visual acuity improvement and a decrease in macular thickness in patients with inflammatory CNV. Of course, further studies are needed to confirm the exact benefit and standardize the optimal treatment regimen.


[Chronic dizziness in a pain patient--pharmacogenomic identification of tramadol as cause].
This casuistic reports on a 59-year-old pain patient taking normal dosage Tramadol as analgetic drug, who suffered from chronic dizziness leading to immobilisation for more than 9 months. On admission to inpatient rehabilitation Tramadol was removed in exchange for morphine sulphate with the unexpected result of a prompt and lasting stop of dizziness. A molecular-genetic investigation showed a duplication in the CYP2D6 gene. This genetic situation caused a quick metabolizing-status for substances dependent on CYP2D6 like Tramadol, which is a prodrug. The quick metabolizing-status resulted in an increased rate of active Tramadol-metabolites which caused the chronic dizziness. Under morphine sulphate which is metabolized independently of CYP2D6, a sufficient analgetic outcome could be achieved. Dizziness did not appear in the patient any longer, and he could be mobilised during rehabilitation. Pharmacogenomic knowledge has helped develop a sustainable concept for rehabilitation of this seriously ill patient, and to put it into practise successfully.


Clinical characteristics and outcomes of critically ill COVID-19 patients in Tokyo: a single-center observational study from the first wave.
Many studies have been published about critically ill coronavirus disease 2019 (COVID-19) during the early phases of the pandemic but the characteristic or survival of critically ill Japanese patients have not yet been investigated. We sought to investigate the characteristics, inflammatory laboratory finding trends, and outcomes among critically ill Japanese patients who were admitted to the intensive care unit (ICU) with the first wave of COVID-19. A retrospective observational study was performed in a single institution in the center of Tokyo. Laboratory-confirmed COVID-19 patients admitted to the ICU from March 19 to April 30, 2020 were included. Trends for significant inflammatory laboratory findings were analyzed. In-hospital death, days of mechanical ventilation or oxygen supplementation, days of ICU or hospital stay were followed until May 26, 2020. Twenty-four patients were included. Median age was 57.5 years, and 79% were male. The neutrophil-to-lymphocyte ratio was elevated to a median of 10.1 on admission and peaked on Day 10 of illness. Seventeen patients were intubated on Day 11 of illness and received mechanical ventilation. One patient underwent extracorporeal membrane oxygenation. The majority (88%) received systemic steroids, including 16 patients who received high dose methylprednisolone (500-1000 mg). Favipiravir was used in 38% of patients. Two patients, including 1 who refused intensive care, died. Eighteen patients were discharged. Median length of ICU and hospital stay for all patients was 6 and 22 days, respectively. Median length of ventilator dependency was 7 days. Four patients underwent a tracheostomy and received prolonged ventilation for more than 21 days. One patient receiving mechanical ventilation died. All survivors discontinued ventilator use. Mortality was remarkably low in our single institutional study. Three survivors received mechanical ventilation for more than 3 weeks. Trends of clinically significant laboratory markers reflected the clinical course of COVID-19.


International Association for the Study of Lung Cancer Computed Tomography Screening Workshop 2011 report.
The International Association for the Study of Lung Cancer (IASLC) Board of Directors convened a computed tomography (CT) Screening Task Force to develop an IASLC position statement, after the National Cancer Institute press statement from the National Lung Screening Trial showed that lung cancer deaths fell by 20%. The Task Force's Position Statement outlined a number of the major opportunities to further improve the CT screening in lung cancer approach, based on experience with cancer screening from other organ sites.The IASLC CT Screening Workshop 2011 further developed these discussions, which are summarized in this report. The recommendation from the workshop, and supported by the IASLC Board of Directors, was to set up the Strategic CT Screening Advisory Committee (IASLC-SSAC). The Strategic CT Screening Advisory Committee is currently engaging professional societies and organizations who are stakeholders in lung cancer CT screening implementation across the globe, to focus on delivering guidelines and recommendations in six specific areas: (i) identification of high-risk individuals for lung cancer CT screening programs; (ii) develop radiological guidelines for use in developing national screening programs; (iii) develop guidelines for the clinical work-up of "indeterminate nodules" resulting from CT screening programmers; (iv) guidelines for pathology reporting of nodules from lung cancer CT screening programs; (v) recommendations for surgical and therapeutic interventions of suspicious nodules identified through lung cancer CT screening programs; and (vi) integration of smoking cessation practices into future national lung cancer CT screening programs.


The Impact of Protein Acetylation/Deacetylation on Systemic Lupus Erythematosus.
Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease in which the body's immune system mistakenly attacks healthy cells. Although the exact cause of SLE has not been identified, it is clear that both genetics and environmental factors trigger the disease. Identical twins have a 24% chance of getting lupus disease if the other one is affected. Internal factors such as female gender and sex hormones, the major histocompatibility complex (MHC) locus and other genetic polymorphisms have been shown to affect SLE, as well as external, environmental influences such as sunlight exposure, smoking, vitamin D deficiency, and certain infections. Several studies have reported and proposed multiple associations between the alteration of the epigenome and the pathogenesis of autoimmune disease. Epigenetic factors contributing to SLE include microRNAs, DNA methylation status, and the acetylation/deacetylation of histone proteins. Additionally, the acetylation of non-histone proteins can also influence cellular function. A better understanding of non-genomic factors that regulate SLE will provide insight into the mechanisms that initiate and facilitate disease and also contribute to the development of novel therapeutics that can specifically target pathogenic molecular pathways.


Determinants of maternal stress during COVID-19 outbreak in Italy and Spain: A cross-cultural investigation.
The present study aims to investigate cross-cultural differences and similarities in maternal and children's adjustment to COVID-19 restrictions in Spain and Italy, with reference to determinants of maternal stress. A total of 950 mothers (45.4% from Spain, n = 432, Mage = 39.6, years old, SD = 5.2 and 54.5% from Italy, n = 518, Mage = 40.5, years, SD = 6.4) of children aged 3-17 years old completed questionnaires on sociodemographic and COVID-19 contextual factors, parenting-related variables, and children externalizing behaviors using an online survey. We examined determinants of parental stress in both countries. Mothers reported a significant increase in parental stress and child externalizing behaviors during COVID-19 home confinement, with more remarkable perceived changes in the Spanish group. Hierarchical linear regressions showed that child age and externalizing behaviors, maternal psychological distress, quality of coparenting and pre-COVID-19 levels of parental stress significantly predicted parental stress in both Italian and Spanish mothers during the pandemic. Results confirmed the negative psychological impact of COVID-19 home confinement on parents and children across countries and revealed common underlying factors responsible for parental stress in Italy and Spain. These findings highlighted the need for communitarian preventive programs to reduce mental health difficulties and parental stress in mothers and behavioral difficulties in children during pandemic restrictions. Particular attention should be paid to young mothers and children, and the key role of positive partner support and coparenting relationships should be considered. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Identification of a New Class of Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitors Followed by a Structure-Activity Relationship Study.
Screening of a small compound library at the three excitatory amino acid transporter subtypes 1-3 (EAAT1-3) resulted in the identification of compound (Z)-4-chloro-3-(5-((3-(2-ethoxy-2-oxoethyl)-2,4-dioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid (1a) that exhibited a distinct preference as an inhibitor at EAAT1 (IC50 20 μM) compared to EAAT2 and EAAT3 (IC50 > 300 μM). This prompted us to subject 1a to an elaborate structure-activity relationship study through the purchase and synthesis and subsequent pharmacological characterization of a total of 36 analogues. Although this effort did not result in analogues with substantially improved inhibitory potencies at EAAT1 compared to that displayed by the hit, it provided a detailed insight into structural requirements for EAAT1 activity of this scaffold. The discovery of this new class of EAAT1-selective inhibitors not only supplements the currently available pharmacological tools in the EAAT field but also substantiates the notion that EAAT ligands not derived from α-amino acids hold considerable potential in terms of subtype-selective modulation of the transporters.


Superoxide dismutase and oxygen toxicity defenses in the genus Neisseria.
Among aerotolerant cells, Neisseria gonorrhoeae is very unusual because despite its obligately aerobic lifestyle and frequent isolation from purulent exudates containing polymorphonuclear leukocytes vigorously evolving O2- and H2O2, it contains no superoxide dismutase (SOD). Strains (14) of N. gonorrhoeae were compared with each other and with strains of Neisseria meningitidis, Neisseria mucosa, and Neisseria subflava under identical growth conditions for their contents of the oxy-protective enzymes catalase, peroxidase, and SOD, as well as respiratory chain proteins and activity. The absence of SOD from N. gonorrhoeae strains was demonstrated under a variety of oxygen-stress conditions. The neisserial species showed very different SOD, catalase, and peroxidase profiles. These profiles correlated well with the tolerance of the species to various intra- and extracellular oxygen insults. The high tolerance of N. gonorrhoeae for extracellular O2- and H2O2 appeared to be due to very high constitutive levels of peroxidase and catalase activity combined with a cell envelope impervious to O2-. Nevertheless, N. gonorrhoeae 19424 was much more sensitive to an intracellular flux of O2- than were the other (SOD-containing) neisserial species. The responses of N. gonorrhoeae and N. meningitidis respiratory and oxy-protective enzymes to growth under high and low oxygen tensions were followed, and a novel response, the apparent repression of the respiratory chain intermediates, respiration, and SOD, peroxidase, and catalase activity, was observed. The gonococcal catalase was partially purified and characterized. The results suggest that the very active terminal oxidase, low pO2 natural habitat, O2-stable catalase, and possibly the high glutathione content of the organism explain its aerobic survival in the absence of SOD.


Taxol-induced neuropathy: chronic effects of local injection.
The long-term neurotoxic effects of taxol, a compound known to promote microtubule protein polymerization, injected subepineurially into rat sciatic nerve were studied up to 10 weeks post-injection. At the site of injection, taxol caused local axonal reactions and degeneration which were causally related to the slow progressive accumulation of microtubules and other axoplasmic constituents. This culminated in the appearance of giant axonal spheroids and profiles similar to the retraction bulbs of Wallerian degeneration. From these axonal bulbs, many of which arose at nodes of Ranvier, groups of regenerating sprouts emanated. During the acute phase of taxol neurotoxicity, some swollen axons were divested of their myelin sheaths and remained demyelinated for many weeks. After 4 weeks, remyelination was apparent along some fibres. In addition to the accumulation of profiles usually associated with retraction bulbs, there was a vast increase in microtubules, some of which were aligned in concentric rings and formed channels for mitochondria. Microtubule anomalies were also visualized in distal portions of affected fibres and in regenerating sprouts. In contrast, Schwann cells displayed microtubule abnormalities only at the site of the lesion where excessive microtubule polymerization caused the displacement of ribosomes from rough endoplasmic reticulum. Distally, Schwann cells were essentially normal. Axonal depletion and regenerating sprouts were noted further downstream in the tibial nerve, and the gastrocnemius muscle showed changes similar to denervation atrophy. These results extend previous observations by demonstrating chronic, reparatory and reversible phenomena, the implications of which are discussed vis à vis axoplasmic transport and nerve regeneration.


[The ocular hypotensive effect and side reactions of domestic clonidine eyedrops].
The single dose test was performed on 100 various cases of glaucoma, with prolonged use t.i.d. for 1 month in 30 cases, for 3 months in 50 cases, for 6 months in 30 cases, and for 1 year in 20 cases. The IOP was lowered by an average 20%, the effect being similar to that of timolol. Clonidine lowered the blood pressure by less than 10%, and the papillary perfusion index was increased rather than decreased. The discomforts, such as thirst, somnolence and dizziness were tolerable and diminished with continued use. The author recommends its wide application in treatment of glaucoma.


[The antibody activity to synthetic C-terminal fragments of the heavy-chain hemagglutinins of influenza virus A subtypes H1 and H3].
C-terminal peptide fragments of the heavy chain (HA1) of influenza virus, subtypes H1 and H3, hemagglutinins were synthesized. Rabbits and guinea pigs immunized with peptides H3 (314-328) and H1 (314-328) conjugates with BSA developed high immune response to conjugated peptides. Solid-phase RIA demonstrated interaction of antisera to peptide H3 (314-328) with A/Aichi/2/68 virus which was inhibited by peptides H3 (314-328) and H3 (317-328) but not by H3 (320-328), that is, antibodies interacted predominantly with amino acids 317-323 HA1. Anti-H3 (314-328)-BSA showed a marked activity in H1 and NT with a number of H3 subtype viruses. Antisera to peptide H1 (314-328) reacted with A/PR/8/34 virus insignificantly and were also inactive in H1 and NT with subtype H1 viruses.


Dopamine transporter-related effects of modafinil in rhesus monkeys.
Modafinil is currently used as a treatment for daytime sleepiness. The objectives of this study were to explore the dopamine transporter (DAT)-related effects of modafinil on behavior and in vivo neurochemistry in rhesus monkeys (Macaca mulatta). The effects of modafinil (3.0-10 mg/kg, i.v.) were evaluated on locomotor activity, reinstatement of cocaine-maintained behavior, extracellular dopamine levels in the caudate nucleus, and DAT occupancy in the dorsal striatum. Eight subjects were fitted with a collar-mounted activity monitor to evaluate sleep-activity cycles, with 4 days of baseline recording preceding an injection of saline or modafinil (3.0-10 mg/kg). The effects of modafinil (3.0-10 mg/kg) and cocaine (0.3 mg/kg) on reinstatement of behavior that was previously maintained under a second-order schedule of i.v. cocaine delivery were tested in a separate group of subjects (n = 6). Finally, the effects of modafinil (3.0-10 mg/kg) on extracellular dopamine levels and DAT occupancy in vivo were characterized using microdialysis and positron emission tomography, respectively, in a within-subjects design (n = 4). Modafinil significantly increased nighttime locomotor activity and reinstated cocaine-maintained behavior but did not affect daytime locomotor activity. Modafinil significantly increased striatal extracellular dopamine levels at a dose that resulted in DAT occupancy of 64.4% (putamen) and 60.2% (caudate). The behavioral and in vivo dopaminergic effects of modafinil are consistent with the profile of a low potency DAT inhibitor and may indicate potential for abuse at high doses.


Assessment and statistical modeling of the relationship between remotely sensed aerosol optical depth and PM2.5 in the eastern United States.
Research in scientific, public health, and policy disciplines relating to the environment increasingly makes use of high-dimensional remote sensing and the output of numerical models in conjunction with traditional observations. Given the public health and resultant public policy implications of the potential health effects of particulate matter (PM*) air pollution, specifically fine PM with an aerodynamic diameter < or = 2.5 pm (PM2.5), there has been substantial recent interest in the use of remote-sensing information, in particular aerosol optical depth (AOD) retrieved from satellites, to help characterize variability in ground-level PM2.5 concentrations in space and time. While the United States and some other developed countries have extensive PM monitoring networks, gaps in data across space and time necessarily occur; the hope is that remote sensing can help fill these gaps. In this report, we are particularly interested in using remote-sensing data to inform estimates of spatial patterns in ambient PM2.5 concentrations at monthly and longer time scales for use in epidemiologic analyses. However, we also analyzed daily data to better disentangle spatial and temporal relationships. For AOD to be helpful, it needs to add information beyond that available from the monitoring network. For analyses of chronic health effects, it needs to add information about the concentrations of long-term average PM2.5; therefore, filling the spatial gaps is key. Much recent evidence has shown that AOD is correlated with PM2.5 in the eastern United States, but the use of AOD in exposure analysis for epidemiologic work has been rare, in part because discrepancies necessarily exist between satellite-retrieved estimates of AOD, which is an atmospheric-column average, and ground-level PM2.5. In this report, we summarize the results of a number of empirical analyses and of the development of statistical models for the use of proxy information, in particular satellite AOD, in predicting PM2.5 concentrations in the eastern United States. We analyzed the spatiotemporal structure of the relationship between PM2.5 and AOD, first using simple correlations both before and after calibration based on meteorology, as well as large-scale spatial and temporal calibration to account for discrepancies between AOD and PM2.5. We then used both raw and calibrated AOD retrievals in statistical models to predict PM2.5 concentrations, accounting for AOD in two ways: primarily as a separate data source contributing a second likelihood to a Bayesian statistical model, as well as a data source on which we could directly regress. Previous consideration of satellite AOD has largely focused on the National Aeronautics and Space Administration (NASA) moderate resolution imaging spectroradiometer (MODIS) and multiangle imaging spectroradiometer (MISR) instruments. One contribution of our work is more extensive consideration of AOD derived from the Geostationary Operational Environmental Satellite East Aerosol/Smoke Product (GOES GASP) AOD and its relationship with PM2.5. In addition to empirically assessing the spatiotemporal relationship between GASP AOD and PM2.5, we considered new statistical techniques to screen anomalous GOES reflectance measurements and account for background surface reflectance. In our statistical work, we developed a new model structure that allowed for more flexible modeling of the proxy discrepancy than previous statistical efforts have had, with a computationally efficient implementation. We also suggested a diagnostic for assessing the scales of the spatial relationship between the proxy and the spatial process of interest (e.g., PM2.5). In brief, we had little success in improving predictions in our eastern-United States domain for use in epidemiologic applications. We found positive correlations of AOD with PM2.5 over time, but less correlation for long-term averages over space, unless we used calibration that adjusted for large-scale discrepancy between AOD and PM2.5 (see sections 3, 4, and 5). Statistical models that combined AOD, PM2.5 observations, and land-use and meteorologic variables were highly predictive of PM2.5 observations held out of the modeling, but AOD added little information beyond that provided by the other sources (see sections 5 and 6). When we used PM2.5 data estimates from the Community Multiscale Air Quality model (CMAQ) as the proxy instead of using AOD, we similarly found little improvement in predicting held-out observations of PM2.5, but when we regressed on CMAQ PM2.5 estimates, the predictions improved moderately in some cases. These results appeared to be caused in part by the fact that large-scale spatial patterns in PM2.5 could be predicted well by smoothing the monitor values, while small-scale spatial patterns in AOD appeared to weakly reflect the variation in PM2.5 inferred from the observations. Using a statistical model that allowed for potential proxy discrepancy at both large and small spatial scales was an important component of our modeling. In particular, when our models did not include a component to account for small-scale discrepancy, predictive performance decreased substantially. Even long-term averages of MISR AOD, considered the best, albeit most sparse, of the AOD products, were only weakly correlated with measured PM2.5 (see section 4). This might have been partly related to the fact that our analysis did not account for spatial variation in the vertical profile of the aerosol. Furthermore, we found evidence that some of the correlation between raw AOD and PM2.5 might have been a function of surface brightness related to land use, rather than having been driven by the detection of aerosol in the AOD retrieval algorithms (see sections 4 and 7). Difficulties in estimating the background surface reflectance in the retrieval algorithms likely explain this finding. With regard to GOES, we found moderate correlations of GASP AOD and PM2.5. The higher correlations of monthly and yearly averages after calibration reflected primarily the improved large-scale correlation, a necessary result of the calibration procedure (see section 3). While the results of this study's GOES reflectance screening and surface reflection correction appeared sensible, correlations of our proposed reflectance-based proxy with PM2.5 were no better than GASP AOD correlations with PM2.5 (see section 7). We had difficulty improving spatial prediction of monthly and yearly average PM2.5 using AOD in the eastern United States, which we attribute to the spatial discrepancy between AOD and measured PM2.5, particularly at smaller scales. This points to the importance of paying attention to the discrepancy structure of proxy information, both from remote-sensing and deterministic models. In particular, important statistical challenges arise in accounting for the discrepancy, given the difficulty in the face of sparse observations of distinguishing the discrepancy from the component of the proxy that is informative about the process of interest. Associations between adverse health outcomes and large-scale variation in PM2.5 (e.g., across regions) may be confounded by unmeasured spatial variation in factors such as diet. Therefore, one important goal was to use AOD to improve predictions of PM2.5 for use in epidemiologic analyses at small-to-moderate spatial scales (within urban areas and within regions). In addition, large-scale PM2.5 variation is well estimated from the monitoring data, at least in the United States. We found little evidence that current AOD products are helpful for improving prediction at small-to-moderate scales in the eastern United States and believe more evidence for the reliability of AOD as a proxy at such scales is needed before making use of AOD for PM2.5 prediction in epidemiologic contexts. While our results relied in part on relatively complicated statistical models, which may be sensitive to modeling assumptions, our exploratory correlation analyses (see sections 3 and 5) and relatively simple regression-style modeling of MISR AOD (see section 4) were consistent with the more complicated modeling results. When assessing the usefulness of AOD in the context of studying chronic health effects, we believe efforts need to focus on disentangling the temporal from the spatial correlations of AOD and PM2.5 and on understanding the spatial scale of correlation and of the discrepancy structure. While our results are discouraging, it is important to note that we attempted to make use of smaller-scale spatial variation in AOD to distinguish spatial variations of relatively small magnitude in long-term concentrations of ambient PM2.5. Our efforts pushed the limits of current technology in a spatial domain with relatively low PM2.5 levels and limited spatial variability. AOD may hold more promise in areas with higher aerosol levels, as the AOD signal would be stronger there relative to the background surface reflectance. Furthermore, for developing countries with high aerosol levels, it is difficult to build statistical models based on PM2.5 measurements and land-use covariates, so AOD may add more incremental information in those contexts. More generally, researchers in remote sensing are involved in ongoing efforts to improve AOD products and develop new approaches to using AOD, such as calibration with model-estimated vertical profiles and the use of speciation information in MISR AOD; these efforts warrant continued investigation of the usefulness of remotely sensed AOD for public health research.


EphB controls NMDA receptor function and synaptic targeting in a subunit-specific manner.
Dynamic regulation of the localization and function of NMDA receptors (NMDARs) is critical for synaptic development and function. The composition and localization of NMDAR subunits at synapses are tightly regulated and can influence the ability of individual synapses to undergo long-lasting changes in response to stimuli. Here, we examine mechanisms by which EphB2, a receptor tyrosine kinase that binds and phosphorylates NMDARs, controls NMDAR subunit localization and function at synapses. We find that, in mature neurons, EphB2 expression levels regulate the amount of NMDARs at synapses, and EphB activation decreases Ca(2+)-dependent desensitization of NR2B-containing NMDARs. EphBs are required for enhanced localization of NR2B-containing NMDARs at synapses of mature neurons; triple EphB knock-out mice lacking EphB1-3 exhibit homeostatic upregulation of NMDAR surface expression and loss of proper targeting to synaptic sites. These findings demonstrate that, in the mature nervous system, EphBs are key regulators of the synaptic localization of NMDARs.


AFM-Based Spin-Exchange Microscopy Using Chiral Molecules.
Local magnetic imaging at nanoscale resolution is desirable for basic studies of magnetic materials and for magnetic logic and memories. However, such local imaging is hard to achieve by means of standard magnetic force microscopy. Other techniques require low temperatures, high vacuum, or strict limitations on the sample conditions. A simple and robust method is presented for locally resolved magnetic imaging based on short-range spin-exchange interactions that can be scaled down to atomic resolution. The presented method requires a conventional AFM tip functionalized with a chiral molecule. In proximity to the measured magnetic sample, charge redistribution in the chiral molecule leads to a transient spin state, caused by the chiral-induced spin-selectivity effect, followed by the exchange interaction with the imaged sample. While magnetic force microscopy imaging strongly depends on a large working distance, an accurate image is achieved using the molecular tip in proximity to the sample. The chiral molecules' spin-exchange interaction is found to be 150 meV. Using the tip with the adsorbed chiral molecules, two oppositely magnetized samples are characterized, and a magnetic imaging is performed. This method is simple to perform at room temperature and does not require high-vacuum conditions.


Opioid Prescribing Trends in Women Following Mastectomy or Breast-Conserving Surgery Before and After the 2014 Federal Reclassification of Hydrocodone.
Given concerns about suboptimal pain management for actively treated cancer patients following the 2014 federal reclassification of hydrocodone, we examined changes in patterns of opioid prescribing among surgical breast cancer patients. Data from a large nationally representative commercial health insurance program from 2009 to 2017 were used to identify women aged 18 years and older who were diagnosed with carcinoma in-situ or malignant breast cancer and received breast-conserving surgery or mastectomy from 2010 to 2016. Generalized linear mixed models were used to estimate the adjusted odds ratio (aOR) for receipt of ≥1-day, >30-day, or ≥ 90-day supply of opioids in the 12 months following surgery adjusting for demographics, cancer treatment-related characteristics, and preoperative opioid use. A total of 60,080 patients were included in the study. Surgically treated breast cancer patients in 2015 (aOR = 0.90, 0.84-0.97) and 2016 (aOR = 0.80, 0.74-0.86) were less likely to receive ≥1-day supply of opioid prescriptions when compared with patients in 2013. Patients who had surgery in 2015 (aOR = 0.89, 0.81-0.98) and 2016 (aOR = 0.80, 0.73-0.87) were also less likely to receive >30-day supply of prescription opioids in the 12 months following surgery. However, only surgical breast cancer patients in 2016 were less likely to receive ≥90-day supply (aOR = 0.86, 0.76-0.98). Surgically treated breast cancer patients are less likely to receive short- and long-term opioid prescriptions following the implementation of hydrocodone rescheduling. Further studies on the potential impact of federal policy on cancer patient pain management are needed. Clinicians and researchers with diverse perspectives should be included as stakeholders during policy development for restricting opioid prescriptions. Stakeholders can identify potential unintended consequences early and help identify methods to mitigate concerns, specifically as it relates to policy that influences how providers manage pain for actively treated cancer patients. This work shows how federal policy may have led to declines in opioid prescribing for breast cancer patients who underwent mastectomy or breast-conserving surgery.


Increased Thyroxin During Therapeutic Hypothermia Predicts Death in Comatose Patients After Cardiac Arrest.
The course and prognostic value of pituitary-thyroid axis hormones is not well studied after cardiac arrest. We aimed to study the prognostic role of the pituitary-thyroid axis response to resuscitation from cardiac arrest before, during and after therapeutic hypothermia. We conducted a retrospective cohort study in consecutive comatose patients after out-of-hospital cardiac arrest who were sampled before, during and up to 48 h after a 24-h period of therapeutic hypothermia in the intensive care unit (ICU). Thyroid-stimulating hormone, total and free thyroxine (T4) and triiodothyronine (T3) were determined and compared between ICU outcome groups. We included twenty-nine patients. TSH levels were comparable in non-survivors (n = 17) and survivors (n = 12). The free T4 levels were higher in non-survivors than in survivors (P = 0.001), whereas the free T3 levels were comparable. All samples' results similarly declined in both outcome groups up to 72 h after start of 24 h hypothermia. ROC curves analyses showed a maximum AUC of 0.83 (P = 0.003) for free T4 at the end of hypothermia with an optimal cut off ≥17.8 pmol/L to obtain 100 % specificity and positive predictive value for non-survival. Non-survival after cardiac arrest, coma, and therapeutic hypothermia following successful resuscitation is associated with a transient increase in free T4, most probably due to inhibition of free T4 to T3 conversion. However, before routine clinical application, external validation of our finding to assess generalizability is warranted.


Detection of human fecal pollution in environmental waters using human mitochondrial DNA and correlation with general and human-associated fecal genetic markers.
Human mitochondrial DNA (mtDNA) genetic markers are abundant in sewage and highly human-specific, suggesting a great potential for the environmental application as human fecal pollution indicators. Limited data are available on the occurrence and co-occurrence of human mtDNA with fecal bacterial markers in surface waters, and how the abundance of these markers is influenced by rain events. A 1-year sampling study was conducted in a suburban watershed impacted by human sewage contamination to evaluate the performance of a human mtDNA-based marker along with the bacterial genetic markers for human-associated Bacteroidales (BacHum and HF183) and Escherichia coli. Additionally, the human mtDNA-based assay was correlated with rain events and other markers. The mtDNA marker was detected in 92% of samples (n = 140) with a mean concentration of 2.96 log10 copies/100 ml throughout the study period. Human mtDNA was detected with greater abundance than human-associated Bacteroidales that could be attributed to differences in the decay of these markers in the environment. The abundance of all markers was positively correlated with rain events, and human mtDNA abundance was significantly correlated with various bacterial markers. In general, these results should support future risk assessment for impacted watersheds, particularly those affected by human fecal pollution, by evaluating the performance of these markers during rain events.


Cost analysis of chronic intestinal failure.
Chronic intestinal failure is a complex medical condition which is associated with high costs. These patients require long-term home parenteral nutrition (HPN) and costs are compounded by frequent admissions for the underlying disease and HPN. However, it is unknown what the specific costs subdivisions are and how they evolve over time. The aim of the study was to evaluate the cost dynamics of HPN care in a cohort of stable, long-term intestinal failure patients. A retrospective analysis of our single-center long-term (>2 years), benign HPN population was performed. All relevant clinical and financial data were collected: costs of hospital admissions, diagnostics, treatments, out-patient clinics, home care, medication, materials and HPN education. The costs were tabulated and assigned by cause (HPN related, underlying disease-related or -unrelated). Patients with complicated intestinal failure (defined as impending loss of vascular access, liver failure or recurrent fluid/electrolyte disorders) were excluded. Data are presented as median (range). Thirty-seven patients (24 female; age 58.6 ± 13.3 years) were included in the study. HPN duration was 5.3 years (2.1-15.1) at 4.3 infusion days per week (1.5-7). Total cost of the first HPN year was €83,503 (35,364-256,780). HPN-related costs accounted for 69% (€57,593) vs 27% for underlying disease-related costs (€22,505) and 4% for disease-unrelated costs (€3065). HPN complications cost €16,077 in the first year and accounted for 31% of HPN costs. The total cost dropped by 15% in the second year to €71,311. This reduction was due to fewer hospital admissions and fewer HPN complications. This trend continued and by year 5 the annual cost was 40% cheaper compared to year 1 (€58,187 vs €83,503). HPN related costs accounted for the majority of the total expenses in IF patients. The costs declined after the first year due to a reduction in complications and hospital admissions.


Adult vaccinations: protecting your patients from avoidable illness.
Influenza vaccine is recommended each year for any adult at high risk for lower respiratory tract complications and death. Also consider immunizing household members of high-risk patients. Those who are susceptible to influenza are also at risk for pneumococcal disease; consider revaccination more than 6 years after the first dose for those at the highest risk of declining antibody levels. Any adult patient whose tetanus immunization status is uncertain should be considered unvaccinated and receive a full three-dose primary series of Td. In the United States, hepatitis B is usually a disease of lifestyle or profession. Rabies vaccine is indicated for your older patients who hunt, trap, explore caves, or travel to endemic areas.


Removing the blocking artifacts of block-based DCT compressed images.
One of the major drawbacks of the block-based DCT compression methods is that they may result in visible artifacts at block boundaries due to coarse quantization of the coefficients. We propose an adaptive approach which performs blockiness reduction in both the DCT and spatial domains to reduce the block-to-block discontinuities. For smooth regions, our method takes advantage of the fact that the original pixel levels in the same block provide continuity and we use this property and the correlation between the neighboring blocks to reduce the discontinuity of the pixels across the boundaries. For texture and edge regions, we apply an edge-preserving smoothing filter. Simulation results show that the proposed algorithm significantly reduces the blocking artifacts of still and video images as judged by both objective and subjective measures.


Optimizing force and velocity: mandible muscle fibre attachments in ants
To be able to perform swift and powerful movements, ant mandible closer muscles are composed of two subpopulations of muscle fibres: fast fibres for rapid actions and slow fibres for forceful biting. All these fibres attach to a sturdy and complex apodeme which conveys force into the mandible base. Fast muscle fibres attach directly to the apodeme. Slow fibres may attach directly or insert at individual thin filament processes of the apodeme which vary in length. Comparisons of different ant species suggest two basic principles underlying the design of mandible muscles. (1) Ants specialized for fast mandible movements generally feature long heads which contain long fast muscle fibres that attach to the apodeme at small angles. Their muscles comprise only a few filament-attached fibres and they maximize speed of action at the expense of force output. (2) Ants performing particularly forceful mandible movements, such as seed cracking, rely on many short parallel muscle fibres contained within a broad head capsule. Their slower muscles incorporate a large proportion of filament-attached fibres. Two simple models explain how the attachment angles are optimized with respect to force and velocity output and how filament-attached fibres help to generate the largest power output from the available head capsule volume.


Babelomics: an integrative platform for the analysis of transcriptomics, proteomics and genomic data with advanced functional profiling.
Babelomics is a response to the growing necessity of integrating and analyzing different types of genomic data in an environment that allows an easy functional interpretation of the results. Babelomics includes a complete suite of methods for the analysis of gene expression data that include normalization (covering most commercial platforms), pre-processing, differential gene expression (case-controls, multiclass, survival or continuous values), predictors, clustering; large-scale genotyping assays (case controls and TDTs, and allows population stratification analysis and correction). All these genomic data analysis facilities are integrated and connected to multiple options for the functional interpretation of the experiments. Different methods of functional enrichment or gene set enrichment can be used to understand the functional basis of the experiment analyzed. Many sources of biological information, which include functional (GO, KEGG, Biocarta, Reactome, etc.), regulatory (Transfac, Jaspar, ORegAnno, miRNAs, etc.), text-mining or protein-protein interaction modules can be used for this purpose. Finally a tool for the de novo functional annotation of sequences has been included in the system. This provides support for the functional analysis of non-model species. Mirrors of Babelomics or command line execution of their individual components are now possible. Babelomics is available at http://www.babelomics.org.


Efficacy of aztreonam in the treatment of skeletal infections due to Pseudomonas aeruginosa.
Twenty-eight patients with skeletal infections due to Pseudomonas aeruginosa were treated with aztreonam during two open, noncomparative, multicenter clinical trials. Ten patients with septic arthritis received 2 g of aztreonam three times a day (modal) for 30 days (mean). The mean follow-up period was 4 weeks. Microbiologic cure was achieved in all 10 patients; complete clinical cure, in eight; and partial clinical cure, in two. Eighteen cases of osteomyelitis were treated with 2 g of aztreonam three times a day (modal) for 40 days (mean), with a mean follow-up period of 6 months. Microbiologic cure was achieved in 17 patients. Relapse occurred 1 month after therapy in one patient. Complete clinical cure was achieved in 13 and partial clinical cure was achieved in five patients. The most common adverse reactions to aztreonam were a transient elevation in levels of hepatic enzymes and transient eosinophilia. Three superinfections and one subsequent infection occurred. These results support use of aztreonam for the treatment of skeletal infections due to P. aeruginosa.


Closely related octopus species show different spatial genetic structures in response to the Antarctic seascape.
Determining whether comparable processes drive genetic divergence among marine species is relevant to molecular ecologists and managers alike. Sympatric species with similar life histories might be expected to show comparable patterns of genetic differentiation and a consistent influence of environmental factors in shaping divergence. We used microsatellite loci to quantify genetic differentiation across the Scotia Arc in three species of closely related benthic octopods, Pareledone turqueti, P. charcoti, and Adelieledone polymorpha. The relative importance of environmental factors (latitude, longitude, depth, and temperature) in shaping genetic structure was investigated when significant spatial genetic structure was uncovered. Isolated populations of P. turqueti and A. polymorpha at these species' range margins were genetically different to samples close to mainland Antarctica; however, these species showed different genetic structures at a regional scale. Samples of P. turqueti from the Antarctic Peninsula, Elephant Island, and Signy Island were genetically different, and this divergence was associated primarily with sample collection depth. By contrast, weak or nonsignificant spatial genetic structure was evident across the Antarctic Peninsula, Elephant Island, and Signy Island region for A. polymorpha, and slight associations between population divergence and temperature or depth (and/or longitude) were detected. Pareledone charcoti has a limited geographic range, but exhibited no genetic differentiation between samples from a small region of the Scotia Arc (Elephant Island and the Antarctic Peninsula). Thus, closely related species with similar life history strategies can display contrasting patterns of genetic differentiation depending on spatial scale; moreover, depth may drive genetic divergence in Southern Ocean benthos.


A randomized comparison of flecainide versus verapamil in paroxysmal supraventricular tachycardia. The Flecainide Multicenter Investigators Group.
Reentrant paroxysmal supraventricular tachycardia (PSVT) are frequently encountered in clinical practice. Verapamil and flecainide have both been successfully used as chronic oral therapy to prevent PSVT recurrences. This open-label, randomized, multicenter study was designed to compare the efficacy and adverse effects of verapamil (median dose, 240 mg/day) versus flecainide (median dose, 200 mg/day) in patients with frequent and symptomatic attacks of PSVT (other than atrial fibrillation or flutter). A total of 121 patients receiving flecainide (n = 63) or verapamil (n = 58) were followed for 8.1 +/- 5.1 and 7.5 +/- 5.4 months, respectively. Response was judged clinically as effective or not by the treating physician. By life table analysis, 11% discontinued flecainide and 19% discontinued verapamil for inefficacy at 1 year (difference not significant). Both groups showed a marked reduction in the frequency of attacks of PSVT. Before therapy, 71% of flecainide patients and 73% of verapamil patients had > or = 2 attacks per month. During therapy, 86% of all flecainide patient-months and 73% of all verapamil patient-months occurred with 0 or 1 attack; 19 (30%) patients on flecainide completed the trial ( > 270 days) without symptomatic attacks versus 7 (13%) of the patients on verapamil (p = 0.026). Both drugs were well tolerated; 19% of the flecainide group discontinued primarily because of adverse effects, compared with 24% discontinuing verapamil for this reason (difference not significant). Both flecainide and verapamil are effective and well tolerated for the prevention of recurrences of PSVT. For patients in whom radiofrequency ablation procedures cannot be performed or are not indicated, either therapy is a reasonable choice for long-term prophylaxis.


The association between left ventricular hypertrophy and consumption of nuts, including peanuts, pine nuts, and almonds.
Studies have reported that nut consumption is potentially beneficial in preventing cardiovascular disease. However, data are insufficient regarding the association between nut consumption and left ventricular hypertrophy (LVH). In the Kangbuk Samsung Health Study, the participants were 34,617 men and 12,257 women who completed a food-frequency questionnaire for nut consumption and received echocardiography. Nut consumption was evaluated only for peanuts, pine nuts, and almonds defining 15 g as one serving/servings dose. Multivariable adjusted odds ratio (OR) and 95% confidence interval (CI) for LVH were evaluated according to the consumption frequency of one serving dose of nut. The frequency of nut consumption was categorized into five groups (<1/month, 1/month-1/week, 1-2/week, 2-4/week, and ≥4/week). The subgroup analysis was conducted by dividing the participants into the following two groups: the nonhypertensive/nondiabetic group and hypertensive or diabetic group. In women, nut consumption ≥2/week had the lower multivariable adjusted OR and 95% CI for LVH (2-4/week: 0.46 [0.26-0.81] and ≥4/week: 0.48 [0.25-0.92]) when compared with nut consumption <1/month. This association was identically observed in the subgroup analysis for women without hypertension and diabetes mellitus (DM) and women with hypertension or DM. However, men did not show the significant association. In women, nut consumption ≥2/week was associated with the decreased probability of LVH. Further research studies should investigate whether the beneficial effect of nut consumption on LV structure results in better cardiovascular prognosis.


Protein phosphatase 2A cooperates with the autophagy-related kinase UNC-51 to regulate axon guidance in Caenorhabditis elegans.
UNC-51 is a serine/threonine protein kinase conserved from yeast to humans. The yeast homolog Atg1 regulates autophagy (catabolic membrane trafficking) required for surviving starvation. In C. elegans, UNC-51 regulates the axon guidance of many neurons by a different mechanism than it and its homologs use for autophagy. UNC-51 regulates the subcellular localization (trafficking) of UNC-5, a receptor for the axon guidance molecule UNC-6/Netrin; however, the molecular details of the role for UNC-51 are largely unknown. Here, we report that UNC-51 physically interacts with LET-92, the catalytic subunit of serine/threonine protein phosphatase 2A (PP2A-C), which plays important roles in many cellular functions. A low allelic dose of LET-92 partially suppressed axon guidance defects of weak, but not severe, unc-51 mutants, and a low allelic dose of PP2A regulatory subunits A (PAA-1/PP2A-A) and B (SUR-6/PP2A-B) partially enhanced the weak unc-51 mutants. We also found that LET-92 can work cell-non-autonomously on axon guidance in neurons, and that LET-92 colocalized with UNC-51 in neurons. In addition, PP2A dephosphorylated phosphoproteins that had been phosphorylated by UNC-51. These results suggest that, by forming a complex, PP2A cooperates with UNC-51 to regulate axon guidance by regulating phosphorylation. This is the first report of a serine/threonine protein phosphatase functioning in axon guidance in vivo.


Effect of the substituent position on the electrochemical, optical and structural properties of donor-acceptor type acridone derivatives.
Three new donor-acceptor (D-A) compounds, positional isomers of phenoxazine-substituted acridone, namely 1-phenoxazine-N-hexylacridone (o-A), 2-phenoxazine-N-hexylacridone (m-A) and 3-phenoxazine-N-hexylacridone (p-A), were synthesized. The synthesized compounds showed interesting, isomerism-dependent electrochemistry. Their oxidation was reversible and their potential (given vs. Fc/Fc+) changed from 0.21 V for o-A to 0.36 V for p-A. In contrast, their reduction was irreversible, isomerism-independent and occurred at rather low potentials (ca. -2.25 to -2.28 V). The electrochemical results led to the following values of the ionization potentials (IPs) and electron affinities (EAs): 5.03 eV and -2.14 eV, 5.15 eV and -2.20 eV, and 5.20 eV and -2.28 eV for o-A, m-A and p-A, respectively. The experimentally obtained values were in very good agreement with those predicted by DFT calculations. All three isomers readily formed single crystals suitable for their structure determination. o-A and p-A crystallized in P1[combining macron] and P21/n space groups, respectively, with one molecule per asymmetric unit, while m-A crystallized in the P21/c space group with two molecules in the asymmetric unit accompanied by disordered solvent molecules. The UV-vis spectra of the studied compounds were isomerism and solvent independent, yielding absorption maxima in the vicinity of 400 nm. Their photoluminescence spectra, in turn, strongly depended on isomerism and the used solvent showing smaller Stokes shifts for the emission bands registered in toluene as compared to the corresponding bands measured in dichloromethane. The photoluminescence quantum yields (φ) were systematically higher for toluene solutions reaching the highest value of 20% for p-A. For all three isomers studied, stationary and time-resolved spectroscopic investigations carried out in toluene at different temperatures revealed spectral features indicating a contribution of thermally activated delayed fluorescence (TADF) to the observed spectroscopic behaviour. The measured photoluminescence quantum yields (φ) were higher for solid state films of pure compounds and for their dispersions in solid matrices (zeonex) than those recorded for toluene and dichloromethane solutions of the studied phenoxazine-N-hexylacridone isomers. The obtained experimental spectroscopic and structural data were confronted with theoretical predictions based on DFT calculations.


Bone marrow histopathology in POEMS syndrome: a distinctive combination of plasma cell, lymphoid, and myeloid findings in 87 patients.
POEMS is an uncommon syndromic disorder characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes. There are few descriptions of the bone marrow pathology of POEMS; therefore, peripheral blood smears and bone marrow aspirates and biopsies from 87 patients (143 total, 67 pretreatment, 76 posttreatment cases) with POEMS were studied. Plasma cell clonality was analyzed by flow cytometry, immunohistochemistry, and/or in situ hybridization. Monotypic plasma cells were detected in 44 pretreatment cases (66%); the majority of plasma cells expressed λ light chain (91%). The monotypic plasma cells typically were present in a background of increased polytypic plasma cells. Lymphoid aggregates were found in 33 (49%) pretreatment cases and in most cases were rimmed by plasma cells (97%). Megakaryocyte hyperplasia (36 cases) and clusters (62 cases) were frequent; however, none of the 43 cases tested had the JAK2(V617F) mutation. In summary, we have identified a novel constellation of features that should strongly suggest POEMS syndrome as part of the differential diagnosis. The constellation of λ-restricted monoclonal gammopathy, plasma cell rimming around lymphoid aggregates, and megakaryocytic hyperplasia in a bone marrow is highly suggestive of this diagnosis, especially in the context of a peripheral neuropathy.


Cardiopulmonary response of the rat to gram-negative bacteremia.
Hemodynamic and respiratory effects of a continuous 5-h intravenous infusion of live Escherichia coli were studied in rats. Control animals were infused with saline. Rats infused with 1.8 +/- 0.4 X 10(10) bacteria/h did not survive a 5-h infusion. These animals developed early hypotension and reduced cardiac output (CO) measured by thermal dilution technique. Rats infused with 8.0 +/- 0.4 X 10(9) bacteria/h survived a 5-h infusion with hypotension and reduced CO occurring later in the course of bacteremia. Heart rate was markedly elevated in both septic groups. Arterial blood gas measurements revealed that partial pressure of O2 was not affected by bacteremia, but partial pressure of CO2 was significantly decreased. Arterial pH remained within the normal range indicating respiratory compensation of a metabolic acidosis. Since hypotension and reduced CO were accompanied by a fall in right atrial pressure (RAP) during bacteremia, a third septic group was studied to evaluate cardiac performance during volume loading. After 3-5 h of bacteremia, a 40% reduction in CO was associated with a significant drop in arterial pressure and RAP. Despite volume loading, ventricular stroke work and arterial pressure were significantly reduced compared with control animals. The results indicate that severe gram-negative bacteremia produces myocardial depression in the rat. This model can be useful for further studies of cardiac dysfunction during sepsis.


AUTOMATICALLY IDENTIFYING WHITE MATTER TRACTS USING CORTICAL LABELS.
Diffusion tensor imaging (DTI) has become a standard clinical procedure in assessing the health of white matter in the brain. Tractography, the tracing of individual fibers in the brain using DTI data, has begun to play a more central role in neuroscience research, particularly in understanding the relationships between brain connectivity and behavior. The measuring of features related to bundles of fibers, i.e., tracts or fasciculi, is currently problematic because of the need for manual interaction. This article presents an algorithm for the automatic identification of selected white matter tracts. It extracts fibers using the FACT algorithm and finds cortical gyral labels using a multi-atlas deformable registration scheme. Tracts are identified as the fibers passing between selected cortical labels. The quality of automatic labels are compared both visually and numerically against a well-accepted manual approach. The automatic approach is shown to be more consistent with conventional definitions of tracts and more repeatable on separate scans of the same subject.


The receding contact line cools down during dynamic wetting.
When a contact line (CL)-where a liquid-vapor interface meets a substrate-is put into motion, it is well known that the contact angle differs between advancing and receding CLs. Using non-equilibrium molecular dynamics simulations, we reveal another intriguing distinction between advancing and receding CLs: while temperature increases at an advancing CL-as expected from viscous dissipation, we show that temperature can drop at a receding CL. Detailed quantitative analysis based on the macroscopic energy balance around the dynamic CL showed that the internal energy change of the fluid due to the change of the potential field along the pathline out of the solid-liquid interface induced a remarkable temperature drop around the receding CL, in a manner similar to latent heat upon phase changes. This result provides new insights for modeling the dynamic CL, and the framework for heat transport analysis introduced here can be applied to a wide range of nanofluidic systems.


Anaerobic Degradation of Non-Methane Alkanes by "Candidatus Methanoliparia" in Hydrocarbon Seeps of the Gulf of Mexico.
Crude oil and gases in the seabed provide an important energy source for subsurface microorganisms. We investigated the role of archaea in the anaerobic degradation of non-methane alkanes in deep-sea oil seeps from the Gulf of Mexico. We identified microscopically the ethane and short-chain alkane oxidizers "Candidatus Argoarchaeum" and "Candidatus Syntrophoarchaeum" forming consortia with bacteria. Moreover, we found that the sediments contain large numbers of cells from the archaeal clade "Candidatus Methanoliparia," which was previously proposed to perform methanogenic alkane degradation. "Ca. Methanoliparia" occurred abundantly as single cells attached to oil droplets in sediments without apparent bacterial or archaeal partners. Metagenome-assembled genomes of "Ca. Methanoliparia" encode a complete methanogenesis pathway including a canonical methyl-coenzyme M reductase (MCR) but also a highly divergent MCR related to those of alkane-degrading archaea and pathways for the oxidation of long-chain alkyl units. Its metabolic genomic potential and its global detection in hydrocarbon reservoirs suggest that "Ca. Methanoliparia" is an important methanogenic alkane degrader in subsurface environments, producing methane by alkane disproportionation as a single organism.IMPORTANCE Oil-rich sediments from the Gulf of Mexico were found to contain diverse alkane-degrading groups of archaea. The symbiotic, consortium-forming "Candidatus Argoarchaeum" and "Candidatus Syntrophoarchaeum" are likely responsible for the degradation of ethane and short-chain alkanes, with the help of sulfate-reducing bacteria. "Ca. Methanoliparia" occurs as single cells associated with oil droplets. These archaea encode two phylogenetically different methyl-coenzyme M reductases that may allow this organism to thrive as a methanogen on a substrate of long-chain alkanes. Based on a library survey, we show that "Ca. Methanoliparia" is frequently detected in oil reservoirs and may be a key agent in the transformation of long-chain alkanes to methane. Our findings provide evidence for the important and diverse roles of archaea in alkane-rich marine habitats and support the notion of a significant functional versatility of the methyl coenzyme M reductase.


[Relaparotomy. Problems of terminology].
The authors discuss the term "relaparotomy" and such its definitions as "early", "delayed", "late", "elective", "targeted", analyze different classifications of relaparotomies, propose their own definition of this term based on objective criteria of general reaction to surgical stress in the form of Seli[symbol: see text] adaptation syndrome which has definite duration (60 days). This fact may be regarded as a clinical criterion of determination of relaparotomy's terms. Surgery may be named as relaparotomy when it is performed in terms of adaptation syndrome (60 days). If surgery is performed after the end of adaptation syndrome it must be regarded as repeated operation.


A SEMI-PARAMETRIC BAYESIAN MODEL OF INTER- AND INTRA-EXAMINER AGREEMENT FOR PERIODONTAL PROBING DEPTH.
Periodontal probing depth is a measure of periodontitis severity. We develop a Bayesian hierarchical model linking true pocket depth to both observed and recorded values of periodontal probing depth, while permitting correlation among measures obtained from the same mouth and between duplicate examiners' measures obtained at the same periodontal site. Periodontal site-specific examiner effects are modeled as arising from a Dirichlet process mixture, facilitating identification of classes of sites that are measured with similar bias. Using simulated data, we demonstrate the model's ability to recover examiner site-specific bias and variance heterogeneity and to provide cluster-adjusted point and interval agreement estimates. We conclude with an analysis of data from a probing depth calibration training exercise.


Photoreactivation compensates for UV damage and restores infectivity to natural marine virus communities.
We investigated the potential for photoreactivation to restore infectivity to sunlight-damaged natural viral communities in offshore (chlorophyll a, < 0.1 microgram liter-1), coastal (chlorophyll a, ca. 0.2 microgram liter-1), and estuarine (chlorophyll a, ca. 1 to 5 micrograms liter-1) waters of the Gulf of Mexico. In 67% of samples, the light-dependent repair mechanisms of the bacterium Vibrio natriegens restored infectivity to natural viral communities which could not be repaired by light-independent mechanisms. Similarly, exposure of sunlight-damaged natural viral communities to > 312-nm-wavelength sunlight in the presence of the natural bacterial communities restored infectivity to 21 to 26% of sunlight-damaged viruses in oceanic waters and 41 to 52% of the damaged viruses in coastal and estuarine waters. Wavelengths between 370 and 550 nm were responsible for restoring infectivity to the damaged viruses. These results indicate that light-dependent repair, probably photoreactivation, compensated for a large fraction of sunlight-induced DNA damage in natural viral communities and is potentially essential for the maintenance of high concentrations of viruses in surface waters.


Diversity matters: the other doctor within the Dutch academic healthcare system.
Over the past year, there has been a worldwide increase in the focus on systemic discrimination and inequitable practices within different societies, particularly concerning race and ethnicity. The inherent (experience of) inequity in racism is notonly limited to individuals but also found in different domains of societal structures, including healthcare and academia. In academia and healthcare organisations, junior Black and Minority Ethnic (BAME) doctors and students regularly find themselves caught between the leaky pipeline phenomenon and hierarchically dependent positions in academic healthcare settings. Voicing their experiences after such encounters is neither an option nor a choice they can do without repercussions. The prejudices, stigmas, implicit biases present within these environments result in segregated practices, where BAME doctors become the 'other' doctor (otherism), and based on their religion, ethnicity, migrant background or physical features are boxed into a specific group or category. The outcome of this exercise (re-) emphasised that more improvement in the Dutch healthcare systems concerning stigmas and biases towards race and ethnicity are needed to promote the inclusion of future BAME doctors and students. A pivotal turn is urgently needed to repair the racial stigmas and biases that have distorted the image of BAME doctors/students, limiting their academic and professional progress. By structurally implementing focused strategies to promote inclusivity, the current gap within healthcare and the participation between non- BAME and BAME-doctors/students can be bridged, inevitably leading to better healthcare services, safer learning environments and a balanced representation of our multicultural societies in healthcare.We argue that increased self-reflection from such critical inquiry will ultimately result in clear and objective understandings of (pre) existent inequitable practices in our societies.


Fabrication of Uniaxially Aligned Silica Nanogrooves with Sub-5 nm Periodicity on Centimeter-Scale Si Substrate Using Poly(dimethylsiloxane) Stamps.
The large-area fabrication of aligned nanopatterns with sub-5 nm feature size is crucial for developing nanodevices. Highly ordered nanostructures fabricated through molecular self-assembly exhibit substantial potential for sub-5 nm patterning techniques. Previously, we had reported the fabrication of silica nanogrooves with sub-5 nm periodicity on a Si substrate by using the outermost surfaces of cylindrical surfactant micelles as a template. However, uniaxial alignment of nanogrooves on the entire substrate surface has not yet been achieved. In this study, uniaxially aligned silica nanogrooves were prepared on the entire surface of a Si substrate (2 cm × 2 cm) by utilizing a poly(dimethylsiloxane) (PDMS) stamp with a striped pattern. The PDMS stamp was placed on the surface of a surfactant thin film precoated on the substrate, although the stamp was not in direct contact with the substrate as in the case of the soft nanoimprint technique. The substrate was then exposed to water vapor, during which cylindrical micelles were aligned in the direction of the guide. Subsequently, by exposing the substrate to an NH3-water vapor mixture, the outermost surfaces of the aligned micelles facing the substrate were replicated with soluble silicate species. The formation of uniaxially aligned nanogrooves on the entire surface of the centimeter-scale substrate was verified by scanning electron microscopy observations and grazing-incidence small-angle X-ray scattering analysis. Thus, herein we provide a simple large-area fabrication method for uniaxially aligned nanopatterns with ultrafine pitch.


Clinical and laboratory features of 78 cases of T-prolymphocytic leukemia.
We describe the clinical and laboratory findings of 78 adult patients with T-prolymphocytic leukemia (T-PLL) studied over the last 12 years. The main disease features were splenomegaly (73%), lymphadenopathy (53%), hepatomegaly (40%), skin lesions (27%), and a high leukocyte count (greater than 100 x 10(9)/L in 75%) with nucleolated prolymphocytes. A variant form with small, less typical cells was recognized in 19%. Membrane markers defined a postthymic phenotype TdT-, CD2+, CD3+, CD5+, CD7+; in 65%, the cells were CD4+ CD8-, in 21%, they coexpressed CD4 and CD8, and, in 13%, they were CD4- CD8+. Serology for human T-cell leukemia/lymphoma virus Type-I (HTLV-I) was negative in the 27 cases investigated. Cytogenetic analysis in 30 cases showed a consistent abnormality of chromosome 14, usually inv (14), with breakpoints at q11 and q32 in 76% of cases. Trisomy 8, including iso8q, was shown in 53%; t (11;14)(q13;q32) was documented in one case; and one had a normal karyotype. The clinical course was progressive with a median survival of 7.5 months. Thirty-one patients were treated with 2' deoxycoformycin and 15 responded (3 complete remissions and 12 partial remissions); the response rate (48%) increased to 58% in patients with a CD4+ CD8- phenotype. The median survival of responders was 16 months and of nonresponders 10 months; other treatments were less effective. T-PLL is a distinct clinico-pathologic entity with aggressive course and characteristic chromosome abnormalities. A subgroup of patients may benefit from deoxycoformycin.


Synthesis and crystal structure of ionic multicomponent complex: ([Cr(I)(PhH)(2)].+))(2)[Co(II)TPP(C(60)(CN)(2))]-[C(60)(CN)(2)](.-).3(o-C(6)H(4)Cl(2)) containing C(60)(CN)(2).- radical anion and sigma-bonded diamagnetic Co(II)TPP(C(60)(CN)(2)) -anion.
The ionic multicomponent complex complex: ([Cr(I)(PhH)(2)].+))(2)[Co(II)TPP(C(60)(CN)(2))]-[C(60)(CN)(2)](.-).3(o-C(6)H(4)Cl(2)) (Co(II)TPP: cobalt (II) tetraphenylporphyrin; Cr(PhH)(2): bis(benzene)chromium; o-C(6)H(4)Cl(2): o-dichlorobenzene) containing CoTPP(C(60)(CN)(2)- anion and C(60)(CN)(2).- radical anion was obtained. The complex has the cage structure with channels, which accommodate Cr(I)(PhH)(2)(.+) and o-C(6)H(4)Cl(2) molecules. For the first time the sigma-bonding of Co(II)TPP to the fullerene radical anion with the essentially shortened Co.C(C(60)(CN)(2)) contact of 2.282 A is observed. The sigma-bonding results in the diamagnetism of Co(II)TPP(C(60)(CN)(2))(-) anion. The nonbonded C(60)(CN)(2)(.-) radical anion retains both the C(2)(v)symmetry and the shape of the molecule. The length of the C(triple bond)N bonds is 1.141 and 1.152 A.


[Oxygen consumption by the yeast-like and filamentous forms of Sporothrix schenckii as measured by polarography].
The study of the oxygen uptake by cultures of Sporothrix schenckii as measured with the Clark electrode has shown that when the fungus was grown in a liquid medium, the atmospheric oxygen went into solution very slowly even when the liquid was rapidly stirred. The partial oxygen pressure was very small after some days of culture (no more than 2 or 3% expressed as the saturated value). Hence, it is postulated that the linear part of the growth curve is due to the dissolved oxygen acting as a limiting factor. When the oxygen uptake by filaments, conidia, or yeasts isplotted against the time the curve variations follow the transformations of the fungus.


Long-term safety and efficacy of bimatoprost solution 0·03% application to the eyelid margin for the treatment of idiopathic and chemotherapy-induced eyelash hypotrichosis: a randomized controlled trial.
Bimatoprost ophthalmic solution 0·03% is approved in several countries for the treatment of eyelash hypotrichosis. Previous trials were limited to 4 months of treatment and primarily idiopathic hypotrichosis. To evaluate the long-term safety and efficacy of bimatoprost in patients with idiopathic or chemotherapy-induced hypotrichosis. This multicentre, double-masked, randomized, parallel-group study included two 6-month treatment periods [treatment period 1 (TP1) and treatment period 2 (TP2)]. Patients with idiopathic hypotrichosis were randomized to three treatment groups: (i) bimatoprost (TP1 and TP2); (ii) bimatoprost (TP1) and vehicle (TP2); and (iii) vehicle (TP1) and bimatoprost (TP2). Patients with chemotherapy-induced hypotrichosis were randomized to two treatment groups: (i) bimatoprost or vehicle (TP1) and (ii) bimatoprost (TP2). Primary end point was a composite of at least a one-grade improvement in investigator-assessed Global Eyelash Assessment and at least a three-point improvement in patient-reported Eyelash Satisfaction Questionnaire Domain 2 at month 4. Secondary measures included digitally assessed eyelash characteristics. The primary efficacy end point was met in both populations (idiopathic responder rate was 40·2% for bimatoprost vs. 6·8% for vehicle; postchemotherapy responder rate was 37·5% for bimatoprost vs. 18·2% for vehicle). Efficacy by month 6 was maintained (idiopathic) or enhanced (postchemotherapy) at 12 months. Treatment effects were maintained for approximately 2 months but markedly diminished 4-6 months following treatment cessation in patients with idiopathic hypotrichosis. No drug-related serious adverse events were reported. Daily treatment with bimatoprost ophthalmic solution 0·03% for 1 year was effective and well tolerated in patients with idiopathic and chemotherapy-induced hypotrichosis.


Effects of intermodal attention on the auditory steady-state response and the event-related potential.
The aim of the present study was to simultaneously measure and compare intermodal attention effects in event-related brain potentials (ERPs) and auditory steady-state responses (ASSRs). For this purpose, 40-Hz amplitude modulated tones and a visual fixation cross were presented concurrently. By means of target detection tasks either on the sounds or on the fixation cross, participants' attention was directed to the respective modality. Attended sounds elicited a negative difference (Nd) in the ERP relative to unattended sounds. Nd was divided into an early and a late part as often observed for intramodal attention. Moreover, attention to the sounds led to a significant enhancement of the ASSR. This modulation of the ASSR by intermodal attention is demonstrated for the first time in the EEG. The present data suggest that ASSRs could provide a useful tool for the investigation of the neural dynamics of intermodal attentional processes.


Complete Absence of the Extrahepatic Biliary Tree in a Newborn With Pigmented Stools.
"Yellow stools in neonatal cholestasis exclude biliary atresia." This conventional wisdom led to the development of the infant stool color card, which alerts parents to seek medical referral when pale stools are observed, a strategy that has been shown to improve survival in infants with biliary atresia (BA). Here, we present a case of a newborn with significant direct hyperbilirubinemia (direct bilirubin level of up to 9.2 mg/dL on day of life 10) who continued to produce colored stools. Whole-genome sequencing results were negative for genetic causes of cholestasis. Hepatobiliary scintigraphy findings were nonexcretory. A liver biopsy specimen revealed cholestasis, ductular hyperplasia, giant cell formation, minimal inflammation, minimal portal or periportal fibrosis, and no evidence of viral changes. On day of life 38, during the exploratory laparotomy, the patient was found to have complete absence of the extrahepatic biliary tree, or biliary aplasia, possibly a rare, severe form of BA. This report aims to increase our vigilance and help prevent diagnostic error in patients with signs and symptoms of BA who may produce pigmented stools. Primary care physicians should hence refer an infant (early and urgently) to a pediatric gastroenterologist for further workup for a direct bilirubin level >1.0 mg/dL with any total bilirubin level, irrespective of the color of the infant's stools.


Can a two-glass urine test or leucocyte esterase test of first-void urine improve syndromic management of male urethritis in southern Thailand?
The goal of this study was to determine whether a urine two-glass test or a leucocyte esterase (LE) test of first-void urine (FVU) improve the sensitivity or specificity of the World Health Organization (WHO) algorithm for the syndromic management of men with urethritis in southern Thailand. A secondary aim was to determine whether infection with Trichomonas vaginalis was sufficiently common to include treatment for it in a syndromic management protocol. One hundred and twenty-nine men with symptoms of urethritis seen at 2 STD clinics in Songkla Province, Thailand were enrolled. Symptoms and signs of each man were recorded and a urethral swab collected for microscopy and culture for Neisseria gonorrhoeae. A two-glass urine test and an LE test of an FVU specimen were performed. The FVU was tested by polymerase chain reaction (PCR) for N. gonorrhoeae, Chlamydia trachomatis and T. vaginalis. Dysuria was a symptom in 78% of men. A urethral discharge was a symptom in 68% but was evident on examination in 95% of the men. The prevalences of infection were 32.6% for N. gonorrhoeae, 23.3% for C. trachomatis, 1.6% for T. vaginalis and 51.9% for any infection. The sensitivities and specificities of urethral discharge on examination, two-glass test and LE test of FVU as indicators of infection with either or both of N. gonorrhoeae or C. trachomatis were 97% and 8%; 57% and 83%; and 59% and 78% respectively. Combinations of urethral discharge on examination and one of the other indicators were more specific but much less sensitive than the presence of discharge alone. Culture for N. gonorrhoeae was found to be only 43% sensitive compared with an expanded gold standard involving a PCR test. Our analysis demonstrates that neither the two-glass test nor the LE test of FVU were useful in improving on the WHO algorithm for management of men with urethritis. T. vaginalis was not common enough to include in a first-line syndromic management protocol for male urethritis. We recommend that, in southern Thailand, men with symptoms of urethritis in whom a urethral discharge is present on examination be offered immediate treatment for both N. gonorrhoeae and C. trachomatis as per the WHO algorithm.


Improved Diet Quality Associates With Reduction in Liver Fat, Particularly in Individuals With High Genetic Risk Scores for Nonalcoholic Fatty Liver Disease.
Dietary modification has been recommended for treatment of nonalcoholic fatty liver disease (NAFLD), although it is not clear whether improving diet quality can prevent its development. We performed a prospective study to examine the association between diet quality change and change in liver fat. We also examined the association between genetic risk score and liver fat change in individuals with different levels of diet quality change. Our study included 1521 participants who attended the seventh and eighth examinations (1998-2001 and 2005-2008) of the second-generation cohort or attended the first and second examinations (2002-2005 and 2008-2011) of the third-generation cohort in the Framingham Heart Study. The self-administered semiquantitative 126-item Harvard food frequency questionnaire was used to determine dietary intake in the year leading up to an examination. We assessed levels of liver fat using liver-phantom ratio (LPR) on computed tomography images from 2002 through 2005 and again from 2008 through 2011. LPR values are inversely related to liver fat: increased LPR indicates decreased liver fat. We examined associations of changes in 2 diet scores, the Mediterranean-style diet score (MDS) and Alternative Healthy Eating Index (AHEI), with changes in liver fat and new-onset fatty liver. We evaluated interactions between diet score change and a weighted genetic risk score for NAFLD, determined based on multiple single-nucleotide polymorphisms identified in genome-wide association studies of NAFLD. The primary outcome was change in LPR between baseline and follow-up measurement. For each 1 standard deviation increase in MDS, the LPR increased (meaning liver fat decreased) by 0.57 (95% confidence interval [CI] 0.27-0.86; P < .001) and the odds for incident fatty liver decreased by 26% (95% CI 10%-39%; P = .002). For each 1 standard deviation increase in AHEI, LPR increased by 0.56 (95% CI 0.29-0.84; P < .001) and the odds for incident fatty liver decreased by 21% (95% CI 5%-35%; P = .02). Increased diet scores were also associated with reduced odds of developing more-advanced fatty liver. Higher genetic risk scores were associated with increased liver fat accumulation in participants who had decreased MDS (P < .001) or AHEI scores (P = .001), but not in those with stable or improved diet scores (P for gene-diet interaction <.001). In an analysis of participants in the Framingham Heart Study, increasing diet quality, determined based on MDS and AHEI scores, is associated with less liver fat accumulation and reduced risk for new-onset fatty liver. An improved diet is particularly important for individuals with a high genetic risk for NAFLD.


Constraints on Biological Mechanism from Disease Comorbidity Using Electronic Medical Records and Database of Genetic Variants.
Patterns of disease co-occurrence that deviate from statistical independence may represent important constraints on biological mechanism, which sometimes can be explained by shared genetics. In this work we study the relationship between disease co-occurrence and commonly shared genetic architecture of disease. Records of pairs of diseases were combined from two different electronic medical systems (Columbia, Stanford), and compared to a large database of published disease-associated genetic variants (VARIMED); data on 35 disorders were available across all three sources, which include medical records for over 1.2 million patients and variants from over 17,000 publications. Based on the sources in which they appeared, disease pairs were categorized as having predominant clinical, genetic, or both kinds of manifestations. Confounding effects of age on disease incidence were controlled for by only comparing diseases when they fall in the same cluster of similarly shaped incidence patterns. We find that disease pairs that are overrepresented in both electronic medical record systems and in VARIMED come from two main disease classes, autoimmune and neuropsychiatric. We furthermore identify specific genes that are shared within these disease groups.


The adequacy of corrective lenses worn by United States Air Force aviators for annual flight medical examinations.
Aviators presenting for annual flight medical examinations at the 379th Strategic Hospital at Wurtsmith Air Force Base were studied to determine the prevalence of substandard visual acuity. The prevalence of the use of outdated (superseded) corrective lenses was also studied. We conducted 342 examinations on different aviators and 92 (26.9%) of these aviators were found to require corrective lenses. There were 23 (6.7%) aviators who were found to have inadequate visual acuity and 14 of these (4.1%) were found to be wearing superseded lenses. The visual screening method prescribed by the United States Air Force did not identify four of the aviators who wore superseded lenses. Three aviators were found to be wearing lenses obtained from civil sources. The study suggests that improvements could be made in U.S. Air Force visual screening and care.


Callous-unemotional traits drive reduced white-matter integrity in youths with conduct problems.
Callous-unemotional (CU) traits represent a significant risk factor for severe and persistent conduct problems in children and adolescents. Extensive neuroimaging research links CU traits to structural and functional abnormalities in the amygdala and ventromedial prefrontal cortex. In addition, adults with psychopathy (a disorder for which CU traits are a developmental precursor) exhibit reduced integrity in uncinate fasciculus, a white-matter (WM) tract that connects prefrontal and temporal regions. However, research in adolescents has not yet yielded similarly consistent findings. We simultaneously modeled CU traits and externalizing behaviors as continuous traits, while controlling for age and IQ, in order to identify the unique relationship of each variable with WM microstructural integrity, assessed using diffusion tensor imaging. We used tract-based spatial statistics to evaluate fractional anisotropy, an index of WM integrity, in uncinate fasciculus and stria terminalis in 47 youths aged 10-17 years, of whom 26 exhibited conduct problems and varying levels of CU traits. Whereas both CU traits and externalizing behaviors were negatively correlated with WM integrity in bilateral uncinate fasciculus and stria terminalis/fornix, simultaneously modeling both variables revealed that these effects were driven by CU traits; the severity of externalizing behavior was not related to WM integrity after controlling for CU traits. These results indicate that WM abnormalities similar to those observed in adult populations with psychopathy may emerge in late childhood or early adolescence, and may be critical to understanding the social and affective deficits observed in this population.


Loss of Rb1 in the gastrointestinal tract of Apc1638N mice promotes tumors of the cecum and proximal colon.
To examine the role of Rb1 in gastrointestinal (GI) tumors, we generated mice with an Apc(1638N) allele, Rb(tm2brn) floxed alleles, and a villin-cre transgene (RBVCA). These animals had exon 19 deleted from Rb1 throughout the GI tract. We have shown previously that Rb1 deficiency is insufficient for GI tumor initiation, with inactivation of an Apc allele capable of overcoming the insufficiency. In this study we demonstrate that RBVCA mice have reduced median survival because of an increase in tumor incidence and multiplicity in the cecum and the proximal colon. Large intestinal tumors are predominantly adenomas, whereas the tumors of the small intestine are a mixture of adenomas and adenocarcinomas. We find truncation mutations to the second Apc allele in tumors of both the large and small intestine. Expression profiles of duodenal and cecal tumors relative to each other show unique gene subsets up and down regulated. Substantial expression patterns compare to human colorectal cancer, including recapitulation of embryonic genes. Our results indicate that Rb1 has significant influence over tumor location in the GI tract, and that both cecal and duodenal tumors initiate through inactivation of Apc. Expression profile analysis indicates the two tumor types differentially regulate distinct sets of genes that are over-expressed in a majority of human colorectal carcinomas.


Interactions of glucose-6-phosphate dehydrogenase deficiency with drug acetylation and hydroxylation reactions.
We hypothesize that the bimodal distribution of hemolytic response by G6PG-deficient individuals to particular drugs such as sulfones may be due to the genetically determined acetylation rate of those drugs. Since metabolism, e.g., hydroxylation, may be required for these drugs to become hemolytic, genetically and environmentally determined variation in hydroxylation of a drug may also contribute to this variability in hemolytic response. To test the possibilities that acetylation and hydroxylation alter the hemolytic potential of these drugs, we incubated G6PG-deficient and normal red cells with mouse liver microsomes at two states of hydroxylase activity (uninduced and induced), an NADPH-generating system, and acetylated or unacetylated drug. We then measured GSH depletion in the cells as an indicator of prelytic cell damage. We found that in the presence of induced (high hydroxylase activity) microsomes, thiazolsulfone (Promizole) or DDS in unacetylated form caused the highest level of GSH depletion in G6PD-deficient red cells. Acetylation protected against GSH depletion. The specificity of the hydroxylation reaction in producing marked GSH depletion was shown by the protective effect of a specific hydroxylation inhibitor. Our results indicate that G6PD-deficient, genetically slow acetylators, having high microsomal activity, would be most susceptible to Promizole- or DDS-induced hemolysis, compared to other metabolic phenotypes. In addition, the bimodality in hemolytic response to Promizole probably corresponds to the bimodal distribution of acetylator phenotype in the population.


A Novel Surface Reconstruction and Display Method for Cardiac PET Imaging.
Positron emission tomography (PET) allows the in vivo assessment of biochemical activity in humans. The newer PET cameras can create several imaging planes, or slices, through an organ inside the body. The interpretation of two-dimensional (2-D) slices of an organ is often difficult for the clinician since he or she has to form a three-dimensional (3-D) mental composite of the structure of interest. We have developed a set of algorithms to reconstruct a functional three-dimensional surface model of the cardiac left ventricle from a set of two-dimensional cross-sectional image slices generated by PET. The theoretical techniques for this reconstruction method are applicable to most organs provided that the appropriate models for the organs are considered. An automatic boundary detection algorithm outlines the surface of the left ventricle from the 2-D images and assigns intensity values to the surface points whose level is proportional to the local activity. A 3-D surface of the intensity levels, with pseudocolor enhancement, is then displayed with the long axis of the heart in a vertical position. Such a display allows the 3-D myocardial tracer uptake to be clearly visualized by the clinician for better diagnosis.


[Effect of ionic composition of incubation medium on inhibition by levorin of amino acid transfer in Candida albicans].
It was demonstrated that K+ and Na+ concentrations in C. albicans cells cultivated on an aerated enriched complex medium do not practically depend on their concentration ratios in the medium. The effect of levorin on the ionic composition of the cells, on the contrary, strongly depends on the composition of the medium. In a Na-containing medium with levorin the bulk of intracellular potassium is substituted by sodium, while in a "potassium" medium no redistribution of the monovalent cations in the cells occurs. The transport of neutral amino acids with a short carbohydrate radical (e. g. glycine, alanine) is largely inhibited by levorin irrespective of the intra- and extracellular concentrations of the movement cations. The inhibition of transport of amino acids with a long carbohydrate radical (e. g. leucine, phenylalanine) by levorin is possibly mediated by its effect on the intracellular concentration of monovalent cations, since in "potassium" medium it is either insignificant or altogether absent. The transfer of neutral amino acids differing in the length of the carbohydrate radical of C. albicans by various systems is discussed.


Evidence for the development of p53 mutations after cytotoxic therapy in a neuroblastoma cell line.
p53 mutations are rare in neuroblastomas at diagnosis perhaps accounting for their initial response to therapy, but advanced neuroblastoma frequently relapses, and it is possible that p53 mutations develop later. Two neuroblastoma cell lines derived from the same patient before [SKNBE(1n)] and after [SKNBE(2c)] cytotoxic therapy were analyzed for the presence of chromosome 17 and p53 genes by fluorescent in situ hybridization, p53 mutations by DNA sequencing, and p53 function after irradiation by studying the transcription of p53-regulated genes, cell cycle arrest, and induction of apoptosis. The SKNBE(1n) cell line was wild-type for p53, had two p53 genes, two copies of chromosome arm 17p and showed functional p53 after irradiation. The SKNBE(2c) cell line derived from the same patient 5 months later at relapse had loss of an entire chromosome 17, resulting in hemizygosity for the p53 locus on 17p and a missense p53 mutation in exon 5, and p53 was not functional after irradiation. The appearance of a p53 mutation in a cell line derived from a relapsed neuroblastoma suggests that this may be a mechanism of resistance to therapy. If p53 mutations develop frequently in relapsed neuroblastoma, cytotoxic agents more sensitive to mutant p53 might be more effective at relapse.


Temporal analysis of the early BMP functions identifies distinct anti-organizer and mesoderm patterning phases.
BMP signaling performs multiple important roles during early embryogenesis. Signaling through the BMP pathway is mediated by different BMP ligands expressed in partially overlapping temporal and spatial patterns. Assignment of different BMP-dependent activities to the individual ligands has relied on the patterns of expression of the various BMP genes. Temporal analysis of BMP signaling prior to and during gastrulation was performed using glucocorticoid-controlled Smad proteins. Overexpression of the BMP-specific Smad1 and Smad5 revealed that suppression of Spemann's organizer formation in Xenopus embryos can only take place by activating the BMP pathway prior to the onset of gastrulation. Blocking BMP signaling with the inhibitory Smad, Smad6, results in dorsalized embryos or secondary axis induction, only when activated up to early gastrula stages. BMP2 efficiently represses organizer-specific transcription from the midblastula transition onwards while BMP4 is unable to prevent the early activation of organizer-specific genes. Manipulation of the BMP pathway during mid/late gastrula affects mesodermal patterning with no external phenotypic effects. These observations suggest that the malformations resulting from inhibition or promotion of organizer formation, ventralized or dorsalized, respectively, are the result of a very early BMP function, through its antagonism of organizer formation. This function is apparently fulfilled by BMP2 and only at its latest phase by BMP4. Subsequently, BMP functions in the patterning of the mesoderm with no apparent phenotypic effects.


Modulation of brassinosteroid-regulated gene expression by Jumonji domain-containing proteins ELF6 and REF6 in Arabidopsis.
Plant steroid hormones, brassinosteroids (BRs), are of great importance for plant growth and development. BRs signal through a cell surface receptor kinase, BRI1, and a GSK3-like kinase, BIN2, to regulate the BES1/BZR1 family of transcription factors, which directly bind to target gene promoters to activate or repress gene expression and mediate BR responses. To understand how BES1 regulates target gene expression, we identified two BES1-interacting proteins, ELF6 (early flowering 6) and its homolog REF6 (relative of early flowering 6), both of which are Jumonji N/C (JmjN/C) domain-containing proteins and were previously found to regulate flowering time. The interactions between BES1 and ELF6/REF6 were confirmed by GST pull-down and BiFC (bimolecular fluorescence complementation) experiments. Mutations in ELF6 or REF6 genes in Arabidopsis lead to BR-related phenotypes, including impaired cell elongation and reduced expression of BR target genes. Chromatin immunoprecipitation (ChIP) experiments indicated that histone 3 lysine 9 (H3K9) methylation status was changed in elf6 and ref6 mutants, consistent with recent findings that many Jmj proteins are histone demethylases. Our results demonstrate that BES1 recruits other transcriptional regulators such as ELF6 and REF6 to regulate target gene expression and coordinate BR responses with other developmental processes such as control of flowering time. Jmj domain-containing histone demethylases are involved in gene expression in many developmental processes and diseases, but how these proteins affect specific pathways is not well understood. Thus, our study establishes an important mechanism by which Jmj domain proteins modulate specific gene expression by interacting with pathway-specific transcription factors such as BES1.


Bacteriophages of Saccharopolyspora erythraea.
Five bacteriophages infecting only Saccharopolyspora erythraea (formerly Streptomyces erythreus) among 43 Streptomyces spp. tested were classified into two groups by phage-host relationships, restriction enzyme mapping, cohesive-end determinations, and Southern hybridizations. phi SE6, the most frequently isolated phage, produced clear plaques on all hosts tested, while phi SE45, phi SE57, phi SE60, and phi SE69 produced turbid plaques. phi SE6 DNA was linear, had a molecular weight of (27.6 +/- 1) X 10(6) and, like the DNAs of phi SE45, phi SE57, and phi SE69, lacked cohesive ends. The characteristic patterns of of ClaI and HindIII restriction digests of phi SE6 DNA and the results of Southern hybridizations with three different ClaI fragments of phi SE6 DNA as probes indicated that phi SE6 DNA was partially circularly permuted and terminally redundant, suggesting that it was packaged by a headful packaging mechanism. Southern hybridization data also showed that phi SE45, phi SE57, and phi SE69 were closely related to phi SE6. phi SE60 DNA, in contrast, had cohesive ends, and restriction mapping plus Southern hybridization data showed that phi SE60 was unrelated to the other four phages.