Ibuprofen protects ventilator-induced lung injury by downregulating Rho-kinase activity in rats.
Ventilator-induced lung injury-(VILI-) induced endothelial permeability is regulated through the Rho-dependent signaling pathway. Ibuprofen inhibits Rho activation in animal models of spinal-cord injury and Alzheimer's disease. The study aims to investigate ibuprofen effects on high tidal volume associated VILI. Twenty-eight adult male Sprague-Dawley rats were randomized to receive a ventilation strategy with three different interventions for 2 h: (1) a high-volume zero-positive end-expiratory pressure (PEEP) (HVZP) group; (2) an HVZP + ibuprofen 15 mg/kg group; and (3) an HVZP + ibuprofen 30 mg/kg group. A fourth group without ventilation served as the control group. Rho-kinase activity was determined by ratio of phosphorylated ezrin, radixin, and moesin (p-ERM), substrates of Rho-kinase, to total ERM. VILI was characterized by increased pulmonary protein leak, wet-to-dry weight ratio, cytokines level, and Rho guanine nucleotide exchange factor (GEF-H1), RhoA activity, p-ERM/total ERM, and p-myosin light chain (MLC) protein expression. Ibuprofen pretreatment significantly reduced the HVZP ventilation-induced increase in pulmonary protein leak, wet-to-dry weight ratio, bronchoalveolar lavage fluid interleukin-6 and RANTES levels, and lung GEF-H1, RhoA activity, p-ERM/total ERM, and p-MLC protein expression. Ibuprofen attenuated high tidal volume induced pulmonary endothelial hyperpermeability. This protective effect was associated with a reduced Rho-kinase activity.


Annual Incidence of Nephrolithiasis among Children and Adults in South Carolina from 1997 to 2012.
The prevalence of nephrolithiasis in the United States has increased substantially, but recent changes in incidence with respect to age, sex, and race are not well characterized. This study examined temporal trends in the annual incidence and cumulative risk of nephrolithiasis among children and adults living in South Carolina over a 16-year period. We performed a population-based, repeated cross-sectional study using the US Census and South Carolina Medical Encounter data, which capture all emergency department visits, surgeries, and admissions in the state. The annual incidence of nephrolithiasis in South Carolina from 1997 to 2012 was estimated, and linear mixed models were used to estimate incidence rate ratios for age, sex, and racial groups. The cumulative risk of nephrolithiasis during childhood and over the lifetime was estimated for males and females in 1997 and 2012. Among an at-risk population of 4,625,364 people, 152,925 unique patients received emergency, inpatient, or surgical care for nephrolithiasis. Between 1997 and 2012, the mean annual incidence of nephrolithiasis increased 1% annually from 206 to 239 per 100,000 persons. Among age groups, the greatest increase was observed among 15-19 year olds, in whom incidence increased 26% per 5 years (incidence rate ratio, 1.26; 95% confidence interval, 1.22 to 1.29). Adjusting for age and race, incidence increased 15% per 5 years among females (incidence rate ratio, 1.15; 95% confidence interval, 1.14 to 1.16) but remained stable for males. The incidence among blacks increased 15% more per 5 years compared with whites (incidence rate ratio, 1.15; 95% confidence interval, 1.14 to 1.17). These changes in incidence resulted in doubling of the risk of nephrolithiasis during childhood and a 45% increase in the lifetime risk of nephrolithiasis for women over the study period. The incidence of kidney stones has increased among young patients, particularly women, and blacks.


Proteomic analysis of cerebrospinal fluid in a fulminant case of multiple sclerosis.
Multiple Sclerosis (MS) is a chronic disease, but in rare fulminant cases rapid progression may lead to death shortly after diagnosis. Currently there is no diagnostic test to predict disease course. The aim of this study was to identify potential biomarkers/proteins related to rapid progression. We present the case history of a 15-year-old male MS patient. Cerebrospinal fluid (CSF) was taken at diagnosis and at the time of rapid progression leading to the patient's death. Using isobaric tag labeling and nanoflow liquid chromatography in conjunction with matrix assisted laser desorption/ionization time of flight tandem mass spectrometry we quantitatively analyzed the protein content of two CSF samples from the patient with fulminant MS as well as one relapsing-remitting (RR) MS patient and one control headache patient, whose CSF analysis was normal. Seventy-eight proteins were identified and seven proteins were found to be more abundant in both fulminant MS samples but not in the RR MS sample compared to the control. These proteins are involved in the immune response, blood coagulation, cell proliferation and cell adhesion. In conclusion, in this pilot study we were able to show differences in the CSF proteome of a rapidly progressing MS patient compared to a more typical clinical form of MS and a control subject.


Biomaterials-Mediated Regulation of Macrophage Cell Fate.
Endogenous regeneration aims to rebuild and reinstate tissue function through enlisting natural self-repairing processes. Promoting endogenous regeneration by reducing tissue-damaging inflammatory responses while reinforcing self-resolving inflammatory processes is gaining popularity. In this approach, the immune system is recruited as the principal player to deposit a pro-reparative matrix and secrete pro-regenerative cytokines and growth factors. The natural wound healing cascade involves many immune system players (neutrophils, macrophages, T cells, B cells, etc.) that are likely to play important and indispensable roles in endogenous regeneration. These cells support both the innate and adaptive arms of the immune system and collectively orchestrate host responses to tissue damage. As the early responders during the innate immune response, macrophages have been studied for decades in the context of inflammatory and foreign body responses and were often considered a cell type to be avoided. The view on macrophages has evolved and it is now understood that macrophages should be directly engaged, and their phenotype modulated, to guide the timely transition of the immune response and reparative environment. One way to achieve this is to design immunomodulating biomaterials that can be placed where endogenous regeneration is desired and actively direct macrophage polarization. Upon encountering these biomaterials, macrophages are trained to perform more pro-regenerative roles and generate the appropriate environment for later stages of regeneration since they bridge the innate immune response and the adaptive immune response. This new design paradigm necessitates the understanding of how material design elicits differential macrophage phenotype activation. This review is focused on the macrophage-material interaction and how to engineer biomaterials to steer macrophage phenotypes for better tissue regeneration.


Inflammation, insulin signaling and cognitive function in aged APP/PS1 mice.
Cognitive dysfunction and neuroinflammation are typical in Alzheimer's disease (AD), but are also associated with normal aging, albeit less severely. Insulin resistance in the brain has been demonstrated in AD patients and is thought to be involved in AD pathophysiology. Using 15-18 month-old APP/PS1 mice, this study measured peripheral and central insulin signaling and sensitivity, inflammatory markers in brain and plasma and oxidative stress and synapse density in the brain. Novel object recognition, Morris water maze and reversal water maze tasks were performed to assess cognitive function in aged APP/PS1 mice and wild type littermates. Glucose tolerance and insulin sensitivity were similar in APP/PS1 mice and wild type controls, however IRS-1 pSer616 was increased in cortex and dentate gyrus of APP/PS1 mice. Recognition and spatial memory was impaired in both APP/PS1 and wild type mice, however learning impairments were apparent in APP/PS1 mice. Expression of GLP-1 receptor, ERK2, IKKβ, mTOR, PKCθ, NF-κB1 and TLR4 was similar between aged APP/PS1 mice and age-matched wild types. Compared to age-matched wild type mice, IFNγ and IL-4 were increased in brains of APP/PS1 mice. These results suggest that normal aging may be associated with enhanced neuroinflammation, oxidative stress, and cognitive decline, however distinctions are apparent in the brain of APP/PS1 mice in terms of inflammation and insulin signaling and in certain cognitive domains. Demarcation of pathological events that distinguish AD from normal aging will allow for improvements in diagnostic tools and the development of more effective therapeutics.


Entanglement and Purification Transitions in Non-Hermitian Quantum Mechanics.
A quantum system subject to continuous measurement and postselection evolves according to a non-Hermitian Hamiltonian. We show that, as one increases the strength of postselection, this non-Hermitian Hamiltonian can undergo a spectral phase transition. On one side of this phase transition (for weak postselection), an initially mixed density matrix remains mixed at all times, and an initially unentangled state develops volume-law entanglement; on the other side, an arbitrary initial state approaches a unique pure state with low entanglement. We identify this transition with an exceptional point in the spectrum of the non-Hermitian Hamiltonian, at which PT symmetry is spontaneously broken. We characterize the transition as well as the nontrivial steady state that emerges at late times in the mixed phase using exact diagonalization and an approximate, analytically tractable mean-field theory; these methods yield consistent conclusions.


Reproducibility, performance, and clinical utility of a genetic risk prediction model for prostate cancer in Japanese.
Prostate specific antigen (PSA) is widely used as a diagnostic biomarker for prostate cancer (PC). However, due to its low predictive performance, many patients without PC suffer from the harms of unnecessary prostate needle biopsies. The present study aims to evaluate the reproducibility and performance of a genetic risk prediction model in Japanese and estimate its utility as a diagnostic biomarker in a clinical scenario. We created a logistic regression model incorporating 16 SNPs that were significantly associated with PC in a genome-wide association study of Japanese population using 689 cases and 749 male controls. The model was validated by two independent sets of Japanese samples comprising 3,294 cases and 6,281 male controls. The areas under curve (AUC) of the model were 0.679, 0.655, and 0.661 for the samples used to create the model and those used for validation. The AUCs were not significantly altered in samples with PSA 1-10 ng/ml. 24.2% and 9.7% of the patients had odds ratio <0.5 (low risk) or >2 (high risk) in the model. Assuming the overall positive rate of prostate needle biopsies to be 20%, the positive biopsy rates were 10.7% and 42.4% for the low and high genetic risk groups respectively. Our genetic risk prediction model for PC was highly reproducible, and its predictive performance was not influenced by PSA. The model could have a potential to affect clinical decision when it is applied to patients with gray-zone PSA, which should be confirmed in future clinical studies.


Inferring the stiffness of unfamiliar objects from optical, shape, and motion cues.
Visually inferring the stiffness of objects is important for many tasks but is challenging because, unlike optical properties (e.g., gloss), mechanical properties do not directly affect image values. Stiffness must be inferred either (a) by recognizing materials and recalling their properties (associative approach) or (b) from shape and motion cues when the material is deformed (estimation approach). Here, we investigated interactions between these two inference types. Participants viewed renderings of unfamiliar shapes with 28 materials (e.g., nickel, wax, cork). In Experiment 1, they viewed nondeformed, static versions of the objects and rated 11 material attributes (e.g., soft, fragile, heavy). The results confirm that the optical materials elicited a wide range of apparent properties. In Experiment 2, using a blue plastic material with intermediate apparent softness, the objects were subjected to physical simulations of 12 shape-transforming processes (e.g., twisting, crushing, stretching). Participants rated softness and extent of deformation. Both correlated with the physical magnitude of deformation. Experiment 3 combined variations in optical cues with shape cues. We find that optical cues completely dominate. Experiment 4 included the entire motion sequence of the deformation, yielding significant contributions of optical as well as motion cues. Our findings suggest participants integrate shape, motion, and optical cues to infer stiffness, with optical cues playing a major role for our range of stimuli.


Low-density lipoprotein level on admission is not associated with postintravenous thrombolysis intracranial hemorrhage in patients with acute ischemic stroke.
Intravenous thrombolysis with the tissue plasminogen activator (tPA) is the gold standard for acute ischemic stroke. However, its application is limited because of the concern of the post-tPA intracranial hemorrhage (ICH). Low low-density lipoprotein (LDL) has been speculated to increase the risk of hemorrhagic transformation after ischemic stroke. However, whether LDL is associated with post-tPA ICH remains controversial. The present study obtained the medical records from Shuang Ho Hospital and retrospectively reviewed for the period between August 2009 and December 2016 to investigate the association between LDL and the risk of post-tPA ICH. The differences were analyzed using the Student's t-test, Fisher's exact test, the univariate and stepwise multiple regression model, and p<0.05 was considered statistically significant. Among 218 patients, post-tPA ICH was noted in 23 (10.5%) patients. Patients with post-tPA ICH tended to have a lower LDL level (ICH group: 102.00±24.56, non-ICH group: 117.02±37.60 mg/dL, p=0.063). However, after adjustment for the factors might affect the risk of post-tPA ICH, such as stroke severity, onset-to-treatment time interval, and atrial fibrillation (AF), LDL level was not associated with post-tPA ICH whereas AF was the only significant factor increased the risk of post-tPA ICH (adjusted OR: 1.177, 95% CI 1.080 to 1.283). In addition, patients with AF had significant lower LDL level and for patients without AF, LDL was not associated with the post-tPA ICH. In conclusion, LDL level is not associated with the risk of post-tPA ICH in Taiwanese patients with stroke.


Comparative genomic, transcriptomic, and proteomic reannotation of human herpesvirus 6.
Human herpesvirus-6A and -6B (HHV-6) are betaherpesviruses that reach > 90% seroprevalence in the adult population. Unique among human herpesviruses, HHV-6 can integrate into the subtelomeric regions of human chromosomes; when this occurs in germ line cells it causes a condition called inherited chromosomally integrated HHV-6 (iciHHV-6). Only two complete genomes are available for replicating HHV-6B, leading to numerous conflicting annotations and little known about the global genomic diversity of this ubiquitous virus. Using a custom capture panel for HHV-6B, we report complete genomes from 61 isolates of HHV-6B from active infections (20 from Japan, 35 from New York state, and 6 from Uganda), and 64 strains of iciHHV-6B (mostly from North America). HHV-6B sequence clustered by geography and illustrated extensive recombination. Multiple iciHHV-6B sequences from unrelated individuals across the United States were found to be completely identical, consistent with a founder effect. Several iciHHV-6B strains clustered with strains from recent active pediatric infection. Combining our genomic analysis with the first RNA-Seq and shotgun proteomics studies of HHV-6B, we completely reannotated the HHV-6B genome, altering annotations for more than 10% of existing genes, with multiple instances of novel splicing and genes that hitherto had gone unannotated. Our results are consistent with a model of intermittent de novo integration of HHV-6B into host germline cells during active infection with a large contribution of founder effect in iciHHV-6B. Our data provide a significant advance in the genomic annotation of HHV-6B, which will contribute to the detection, diversity, and control of this virus.


A controlled trial of an expert system and self-help manual intervention based on the stages of change versus standard self-help materials in smoking cessation.
To examine the population impact and effectiveness of the Pro-Change smoking cessation course based on the Transtheoretical Model (TTM) compared to standard self-help smoking cessation literature. Randomized controlled trial. Sixty-five West Midlands general practices. Randomly sampled patients recorded as smokers by their general practitioners received an invitation letter and 2471 current smokers agreed. Responders were randomized to one of four interventions. The control group received standard self-help literature. In the Manual intervention group, participants received the Pro-Change system, a self-help workbook and three questionnaires at 3-monthly intervals, which generated individually tailored feedback. In the Phone intervention group, participants received the Manual intervention plus three telephone calls. In the Nurse intervention group, participants received the Manual intervention plus three visits to the practice nurse. Biochemically confirmed point prevalence of being quit and 6-month sustained abstinence, 12 months after study commencement. A total of 9.1% of registered current smokers participated, of whom 83.0% were not ready to quit. Less than half of participants returned questionnaires to generate second and third individualized feedback. Telephone calls reached 75% of those scheduled, but few participants visited the nurse. There were small differences between the three Pro-Change arms. The odds ratio (95% confidence intervals) for all Pro-Change arms combined versus the control arm were 1.50 (0.85-2.67) and 1.53 (0.76-3.10), for point prevalence and 6-month abstinence, respectively. This constitutes 2.1% of the TTM group versus 1.4% of the control group achieving confirmed 6-month sustained abstinence. There was no statistically significant benefit of the intervention apparent in this trial and the high relapse of quitters means that any population impact is small.


Long-term engraftment of multipotent mesenchymal stromal cells that differentiate to form myogenic cells in dogs with Duchenne muscular dystrophy.
Duchenne muscular dystrophy (DMD) is an incurable genetic disease with early mortality. Multipotent mesenchymal stromal cells (MSCs) are of interest because of their ability to differentiate to form myogenic cells in situ. In the present study, methods were developed to expand cultures of MSCs and to promote the myogenic differentiation of these cells, which were then used in a new approach for the treatment of DMD. MSC cultures enriched in CD271(+) cells grew better than CD271-depleted cultures. The transduction of CD271(+) MSCs with MyoD caused myogenic differentiation in vitro and the formation of myotubes expressing late myogenic markers. CD271(+) MSCs in the myogenic cell lineage transplanted into dog leukocyte antigen (DLA)-identical dogs formed clusters of muscle-like tissue. Intra-arterial injection of the CD271(+) MSCs resulted in engraftment at the site of the cardiotoxin (CTX)-injured muscle. Dogs affected by X-linked muscular dystrophy in Japan (CXMD(J)) treated with an intramuscular injection of CD271(+) MSCs similarly developed muscle-like tissue within 8-12 weeks in the absence of immunosuppression. In the newly formed tissues, developmental myosin heavy chain (dMyHC) and dystrophin were upregulated. These findings demonstrate that a cell transplantation strategy using CD271(+) MSCs may offer a promising treatment approach for patients with DMD.


Antenatal maternal anxiety predicts variations in neural structures implicated in anxiety disorders in newborns.
Antenatal maternal anxiety predicts offspring neurodevelopment and psychopathology, although the degree to which these associations reflect postnatal influences is unclear. To limit this possibility, we assessed newborn neuronal microstructures using diffusion tensor imaging (DTI) and assessed neonatal microstructure variation in relation to antenatal anxiety and in prediction of infant socio-emotional behavior at age 1 year. Dyads were drawn from the Growing Up in Singapore Towards Healthy Outcomes (GUSTO) cohort, and included mothers who completed the Speilberger State-Trait Anxiety Inventory (STAI) at 26 weeks gestation (scoring >90, n = 20; scoring <70, n = 34) and their neonates (5-17 days postnatal) who took part in DTI. Antenatal anxiety predicted variation in fractional anisotropy (FA) of regions important to cognitive-emotional responses to stress (i.e., the right insula and dorsolateral prefrontal cortex), sensory processing (e.g., right middle occipital), and socio-emotional function (e.g., the right angular gyrus, uncinate fasciculus, posterior cingulate, and parahippocampus). In a subset of infants with Infant Toddler Socio-Emotional Assessment (ITSEA) data, some of these right lateralized clusters predicted infant internalizing (e.g., insula: β = 0.511, p = .03) but not externalizing behavior 1 year later, although these analyses failed to withstand the correction for multiple comparisons. These findings suggest the need for larger-scale investigations of the role that corticolimbic structures play in regulating cognitive-emotional responses to threat, and potentially in mediating the cross-generational transmission of anxiety, as well as in underscoring the importance of early mother-infant intervention programs.


New approaches in primary central nervous system lymphoma.
Primary central nervous system lymphoma (PCNSL) has long been associated with an inferior prognosis compared to other aggressive non-Hodgkin's lymphomas (NHLs). However, during the past 10 years an accumulation of clinical experience has demonstrated that long-term progression-free survival (PFS) can be attained in a major proportion of PCNSL patients who receive dose-intensive consolidation chemotherapy and avoid whole brain radiotherapy. One recent approach that has reproducibly demonstrated efficacy for newly diagnosed PCNSL patients is an immunochemotherapy combination regimen used during induction that consists of methotrexate, temozolomide, and rituximab followed by consolidative infusional etoposide plus high-dose cytarabine (EA), administered in first complete remission (CR). Other high-dose chemotherapy-based consolidative regimens have shown efficacy as well. Our goal in this review is to update principles of diagnosis and management as well as data regarding the molecular pathogenesis of PCNSL, information that may constitute a basis for development of more effective therapies required to make additional advances in this phenotype of aggressive NHL.


U.S. Return Migration and the Decline in Southern Black Disadvantage, 1970-2000.
This study investigates how the Return Migration altered racial inequality in poverty in the American South. I disaggregate southern poverty into its separate constituents using household data from the Integrated Public Use Microdata Series (IPUMS) for 1970 through 2000. The prevalence of poverty declined most dramatically for black southern households and the racial gap in poverty narrowed to the extent that previous substantial regional differences disappeared. A central focus is the contrast between higher poverty and inequality among migrants who returned to their birth state relative to other southern-born migrants who returned to the South. The migration experience is diverse and has conflicting consequences for racial inequality; for some, migration maintained economic vulnerability. Given the complex force of migration, I conclude that a nuanced theoretical approach to migration that gives weight to economic and noneconomic motivations is critical to understand the racial dimensions of migration and the associated changes in racial inequality.


Optical fiber relative humidity sensor based on FBG incorporated thin-core fiber modal interferometer.
A new fiber-optic relative humidity (RH) sensor based on a thin-core fiber modal interferometer (TCFMI) with a fiber Bragg grating (FBG) in between is presented. Poly (N-ethyl-4-vinylpyridinium chloride) (P4VP·HCl) and poly (vinylsulfonic acid, sodium salt) (PVS) are layer-by-layer deposited on the side surface of the sensor for RH sensing. The fabrication of the sensing nanocoating is characterized by using UV-vis absorption spectroscopy, quartz crystal microbalance (QCM) and scanning electron microscopy (SEM). The incorporation of FBG in the middle of TCFMI can compensate the cross sensitivity of the sensor to temperature. The proposed sensor can detect the RH with resolution of 0.78% in a large RH range at different temperatures. A linear, fast and reversible response has been experimentally demonstrated.


Acetoacetate metabolism in infant and adult rat brain in vitro.
1. Acetoacetate or dl-beta-hydroxybutyrate increases the rate of oxygen consumption to a smaller extent than that brought about by glucose or pyruvate in adult rat brain-cortex slices but to the same extent as that in infant rat brain-cortex slices. 2. The rate of (14)CO(2) evolution from [1-(14)C]glucose considerably exceeds that from [6-(14)C]glucose in respiring infant rat brain-cortex slices, in contrast with adult brain-cortex slices, suggesting that the hexose monophosphate shunt operates at a greater rate in the infant rat brain than in the adult rat brain. 3. The rate of (14)CO(2) evolution from [3-(14)C]acetoacetate or dl-beta-hydroxy[3-(14)C]butyrate, in the absence of glucose, is the same in infant rat brain slices as in adult rat brain slices. It exceeds that from [2-(14)C]glucose in infant rat brain but is less than that from [2-(14)C]glucose in adult rat brain. 4. Acetoacetate is oxidized in the brain through the operation of the citric acid cycle, as shown by the accelerating effect of glucose on acetoacetate oxidation in adult brain slices, by the inhibitory effects of malonate in both infant and adult brain slices and by its conversion into glutamate and related amino acids in both tissues. 5. Acetoacetate does not affect glucose utilization in adult or infant brain slices. It inhibits the rate of (14)CO(2) formation from [2-(14)C]glucose or [U-(14)C]-glucose the effect not being wholly due to isotopic dilution. 6. Acetoacetate inhibits non-competitively the oxidation of [1-(14)C]pyruvate, the effect being attributed to competition between acetyl-CoA and CoA for the pyruvate-oxidation system. 7. Acetoacetate increases the rate of aerobic formation of lactate from glucose with both adult and infant rat brain slices. 8. The presence of 0.1mm-2,4-dinitrophenol diminishes but does not abolish the rate of (14)CO(2) formation from [3-(14)C]acetoacetate in rat brain slices. This points to the participation of ATP in the process of oxidation of acetoacetate in infant or adult rat brain. 9. The presence of 5mm-d-glutamate inhibits the rate of (14)CO(2) formation from [3-(14)C]acetoacetate, in the presence or absence of glucose. 10. Labelled amino acids are formed from [3-(14)C]acetoacetate in both adult and infant rat brain-cortex slices, but the amounts are smaller than those found with [2-(14)C]glucose in adult rat brain and greater than those found with [2-(14)C]glucose in infant rat brain. 11. Acetoacetate is not as effective as glucose as a precursor of acetylcholine in adult rat brain but is as effective as glucose in infant rat brain slices. 12. Acetoacetate or beta-hydroxybutyrate is a more potent source of acetyl-CoA than is glucose in infant rat brain slices but is less so in adult rat brain slices.


Experiments on salt fingers in a hele shaw cell.
"Salt fingers" are generated when a slowly diffusing solute overlies a more rapidly diffusing solute in a gravitationally stable fluid. The phenomenon is important in many areas of science; for example, it affects the temperature and salinity structure in the upper half of the ocean, the production of crystals when liquid alloys solidify, and the distribution of properties in magma chambers below the earth's crust. The evolution of a salt finger from initial instability to a fully developed feature is difficult to follow in a fluid because of the close-packed array of cells that is formed. However, when the fluid is contained in a Hele Shaw cell, individual fingers occupy the entire gap width, thereby enabling the experimenter to monitor and record the evolution much more easily. The instability of an array of wide fingers to disturbances that lead to (preferred) smaller scales is documented in a sequence of photographs, and a qualitative, physically consistent argument is offered to explain the instability.


Standardisation or modelling of mortality rates.
To compare the results obtained when estimating a standardised rate using the conventional technique of stratified analysis and using Poisson regression, and to evaluate the speed of the two techniques in making the calculation. Cross sectional study. The trend in motor vehicle accident mortality in males from 1985 to 1992 in Spain was compared using stratified analysis and Poisson regression. In the stratified analysis the calculations were made using a specially designed spreadsheet while in the Poisson regression the statistical program used was EGRET. The stratified analysis took two hours and the Poisson regression 15 minutes to complete. In the stratified analysis a single estimate for each year was obtained, whereas the model of Poisson regression that best fitted the data included an interaction term between age and year. Poisson regression can be considered a serious alternative to stratified analysis when the objective is to compare mortality rates standardised by one or two variables.


A cautionary signal from the Red Sea on the impact of increased dust activity on marine microbiota.
Global climate change together with growing desertification is leading to increased dust emissions to the atmosphere, drawing attention to possible impacts on marine ecosystems receiving dust deposition. Since microorganisms play important roles in maintaining marine homeostasis through nutrient cycling and carbon flow, detrimental changes in the composition of marine microbiota in response to increased dust input could negatively impact marine health, particularly so in seas located within the Global Dust Belt. Due to its strategic location between two deserts and unique characteristics, the Red Sea provides an attractive semi-enclosed "megacosm" to examine the impacts of large dust deposition on the vastly diverse microbiota in its exceptionally warm oligotrophic waters. We used culture-independent metagenomic approaches to assess temporal changes in the Red Sea microbiota in response to two severe sandstorms, one originated in the Nubian Desert in the summer 2016 and a second one originated in the Libyan Desert in the spring 2017. Despite differences in sandstorm origin and meteorological conditions, both sandstorms shifted bacterial and Archaeal groups in a similar mode. In particular, the relative abundance of autotrophic bacteria declined while those of heterotrophic bacteria, particularly Bacteroidetes, and Archaea increased. The changes peaked within six days from the start of sandstorms, and the community recovered the original assemblage within one month. Our results suggest that increased dust emission with expanding desertification could lead to undesirable impacts in ocean function, enhancing heterotrophic processes while reducing autotrophic ones, thereby affecting the marine food web in seas receiving dust deposition.


Marijuana and chronic obstructive lung disease: a population-based study.
Our aim was to determine the combined and independent effects of tobacco and marijuana smoking on respiratory symptoms and chronic obstructive pulmonary disease (COPD) in the general population. We surveyed a random sample of 878 people aged 40 years or older living in Vancouver, Canada, about their respiratory history and their history of tobacco and marijuana smoking. We performed spirometric testing before and after administration of 200 microg of salbutamol. We examined the association between tobacco and marijuana smoking and COPD. The prevalence of a history of smoking in this sample was 45.5% (95% confidence interval [CI] 42.2%-48.8%) for marijuana use and 53.1% (95% CI 49.8%-56.4%) for tobacco use. The prevalence of current smoking (in the past 12 months) was 14% for marijuana use and 14% for tobacco use. Compared with nonsmokers, participants who reported smoking only tobacco, but not those who reported smoking only marijuana, experienced more frequent respiratory symptoms (odds ratio [OR] 1.50, 95% CI 1.05-2.14) and were more likely to have COPD (OR 2.74, 95% CI 1.66-4.52). Concurrent use of marijuana and tobacco was associated with increased risk (adjusted for age, asthma and comorbidities) of respiratory symptoms (OR 2.39, 95% CI 1.58-3.62) and COPD (OR 2.90, 95% CI 1.53-5.51) if the lifetime dose of marijuana exceeded 50 marijuana cigarettes. The risks of respiratory symptoms and of COPD were related to a synergistic interaction between marijuana and tobacco. Smoking both tobacco and marijuana synergistically increased the risk of respiratory symptoms and COPD. Smoking only marijuana was not associated with an increased risk of respiratory symptoms or COPD.


Chemical and sensory analysis of strawberry flavoured yogurt supplemented with an algae oil emulsion.
A yogurt mix (2 g fat and 17g solids/100 g) was supplemented with an algae oil emulsion to provide 500 mg omega-3 fatty acids per 272 g serving of yogurt white mass. The emulsion was added to the yogurt mix either before or after the homogenization step and prior to pasteurization. It was then flavoured with a strawberry fruit base and fermented and stored for up to three weeks. The oxidative deterioration of the products was determined by hydroperoxide measurements and by trained and consumer sensory evaluations. The hydroperoxide content of the supplemented yogurts increased over the storage treatment and was unaffected by the stage of addition. The trained panel could distinguish a stronger fishy flavour in both of the supplemented yogurts after 22 days storage, but the consumer panel rated both control and supplemented samples similarly, as 'moderately liked'.


Simultaneous humoral and cellular immune response against cancer-testis antigen NY-ESO-1: definition of human histocompatibility leukocyte antigen (HLA)-A2-binding peptide epitopes.
A growing number of human tumor antigens have been described that can be recognized by cytotoxic T lymphocytes (CTLs) in a major histocompatibility complex (MHC) class I-restricted fashion. Serological screening of cDNA expression libraries, SEREX, has recently been shown to provide another route for defining immunogenic human tumor antigens. The detection of antibody responses against known CTL-defined tumor antigens, e.g., MAGE-1 and tyrosinase, raised the question whether antibody and CTL responses against a defined tumor antigen can occur simultaneously in a single patient. In this paper, we report on a melanoma patient with a high-titer antibody response against the "cancer-testis" antigen NY-ESO-1. Concurrently, a strong MHC class I-restricted CTL reactivity against the autologous NY-ESO-1-positive tumor cell line was found. A stable CTL line (NW38-IVS-1) was established from this patient that reacted with autologous melanoma cells and with allogeneic human histocompatibility leukocyte antigen (HLA)-A2(-), NY-ESO-1-positive, but not NY-ESO-1-negative, melanoma cells. Screening of NY-ESO-1 transfectants with NW38-IVS-1 revealed NY-ESO-1 as the relevant CTL target presented by HLA-A2. Computer calculation identified 26 peptides with HLA-A2-binding motifs encoded by NY-ESO-1. Of these, three peptides were efficiently recognized by NW38-IVS-1. Thus, we show that antigen-specific humoral and cellular immune responses against human tumor antigens may occur simultaneously. In addition, our analysis provides a general strategy for identifying the CTL-recognizing peptides of tumor antigens initially defined by autologous antibody.


Nondestructive detection of an optical photon.
All optical detectors to date annihilate photons upon detection, thus excluding repeated measurements. Here, we demonstrate a robust photon detection scheme that does not rely on absorption. Instead, an incoming photon is reflected from an optical resonator containing a single atom prepared in a superposition of two states. The reflection toggles the superposition phase, which is then measured to trace the photon. Characterizing the device with faint laser pulses, a single-photon detection efficiency of 74% and a survival probability of 66% are achieved. The efficiency can be further increased by observing the photon repeatedly. The large single-photon nonlinearity of the experiment should enable the development of photonic quantum gates and the preparation of exotic quantum states of light.


Chronic disease surveillance systems within the US Associated Pacific Island jurisdictions.
In recent years, illness and death due to chronic disease in the US Associated Pacific Islands (USAPI) jurisdictions have dramatically increased. Effective chronic disease surveillance can help monitor disease trends, evaluate public policy, prioritize resource allocation, and guide program planning, evaluation, and research. Although chronic disease surveillance is being conducted in the USAPI, no recently published capacity assessments for chronic disease surveillance are available. The objective of this study was to assess the quality of existing USAPI chronic disease data sources and identify jurisdictional capacity for chronic disease surveillance. The assessment included a chronic disease data source inventory, literature review, and review of surveillance documentation available from the web or through individual jurisdictions. We used the World Health Organization's Health Metric Network Framework to assess data source quality and to identify jurisdictional capacity. Results showed that USAPI data sources are generally aligned with widely accepted chronic disease surveillance indicators and use standardized data collection methodology to measure chronic disease behavioral risks, preventive practices, illness, and death. However, all jurisdictions need to strengthen chronic disease surveillance through continued assessment and expanded support for valid and reliable data collection, analysis and reporting, dissemination, and integration among population-based and institution-based data sources. For sustained improvement, we recommend investment and technical assistance in support of a chronic disease surveillance system that integrates population-based and institution-based data sources. An integrated strategy that bridges and links USAPI data sources can support evidence-based policy and population health interventions.


Temperature-Controlled Liquid-Liquid Phase Separation of Disordered Proteins.
The liquid-liquid phase separation (LLPS) of intrinsically disordered proteins (IDPs) is a commonly observed phenomenon within the cell, and such condensates are also highly attractive for applications in biomaterials and drug delivery. A better understanding of the sequence-dependent thermoresponsive behavior is of immense interest as it will aid in the design of protein sequences with desirable properties and in the understanding of cellular response to heat stress. In this work, we use a transferable coarse-grained model to directly probe the sequence-dependent thermoresponsive phase behavior of IDPs. To achieve this goal, we develop a unique knowledge-based amino acid potential that accounts for the temperature-dependent effects on solvent-mediated interactions for different types of amino acids. Remarkably, we are able to distinguish between more than 35 IDPs with upper or lower critical solution temperatures at experimental conditions, thus providing direct evidence that incorporating the temperature-dependent solvent-mediated interactions to IDP assemblies can capture the difference in the shape of the resulting phase diagrams. Given the success of the model in predicting experimental behavior, we use it as a high-throughput screening framework to scan through millions of disordered sequences to characterize the composition dependence of protein phase separation.


Using Video from Mobile Phones to Improve Pediatric Phone Triage in an Underserved Population.
Video-capable mobile phones are widely available, but few studies have evaluated their use in telephone triage for pediatric patients. We assessed the feasibility, acceptability, and utility of videos sent via mobile phones to enhance pediatric telephone triage for an underserved population with asthma. We recruited children who presented to an urban pediatric emergency department with an asthma exacerbation along with their parent/guardian. Parents and the research team each obtained a video of the child's respiratory exam, and the research team conducted a concurrent in-person rating of respiratory status. We measured the acceptability of families sending videos as part of telephone triage (survey) and the feasibility of this approach (rates of successful video transmission by parents to the research team). To estimate the utility of the video in appropriately triaging children, four clinicians reviewed each video and rated whether they found the video reassuring, neutral, or raising concerns. Among 60 families (78% Medicaid, 85% Black), 80% of parents reported that sending a video would be helpful and 68% reported that a nurse's review of a video would increase their trust in the triage assessment. Most families (75%) successfully transmitted a video to the research team. All clinician raters found the video reassuring regarding the severity of the child's asthma exacerbation for 68% of children. Obtaining mobile phone videos for telephone triage is acceptable to families, feasible, and may help improve the quality of telephone triage in an urban, minority population.


Silicifying biofilm exopolymers on a hot-spring microstromatolite: templating nanometer-thick laminae.
Exopolymeric substances (EPS) are an integral component of microbial biofilms; however, few studies have addressed their silicification and preservation in hot-spring deposits. Through comparative analyses with the use of a range of microscopy techniques, we identified abundant EPS significant to the textural development of spicular, microstromatolitic, siliceous sinter at Champagne Pool, Waiotapu, New Zealand. Examination of biofilms coating sinter surfaces by confocal laser scanning microscopy (CLSM), environmental scanning electron microscopy (ESEM), cryo-scanning electron microscopy (cryo-SEM), and transmission electron microscopy (TEM) revealed contraction of the gelatinous EPS matrix into films (approximately 10 nm thick) or fibrillar structures, which is common in conventional SEM analyses and analogous to products of naturally occurring desiccation. Silicification of fibrillar EPS contributed to the formation of filamentous sinter. Matrix surfaces or dehydrated films templated sinter laminae (nanometers to microns thick) that, in places, preserved fenestral voids beneath. Laminae of similar thickness are, in general, common to spicular geyserites. This is the first report to demonstrate EPS templation of siliceous stromatolite laminae. Considering the ubiquity of biofilms on surfaces in hot-spring environments, EPS silicification studies are likely to be important to a better understanding of the origins of laminae in other modern and ancient stromatolitic sinters, and EPS potentially may serve as biosignatures in extraterrestrial rocks.


Maternal risk factors and anaemia in pregnancy: a prospective retrospective cohort study.
Anaemia in pregnancy is still a concern during the reproductive period, as it is associated with increased maternal and perinatal mortality and morbidity. This study examined the maternal risk factors associated with increased prevalence of anaemia among antenatal and postnatal women. A prospective-retrospective cohort approach was carried out among 1,077 antenatal and 1,000 postnatal women. The haemoglobin was estimated using the cyanmethaemoglobin method. The maternal factors included were age, parity, education, socioeconomic status, spacing, history of bleeding, worm infestation, period of gestation, knowledge regarding anaemia in pregnancy, food selection ability and compliance to iron supplementation. Of the 1,077 antenatal women studied, 540 were anaemic. Among the 1,000 postnatal women, the prevalence was 537 (53.7%). The high prevalence was strongly associated with low socioeconomic status (OR 1.409 [1.048-1.899]; p < 0.023) which affected their knowledge and health seeking behaviour in both the groups. Hence it can be concluded that empowering women in terms of education and economic status is the key factor in combating anaemia in pregnancy to prevent the vicious cycle of associated problems.


VNTR allele frequency distributions under the stepwise mutation model: a computer simulation approach.
Variable numbers of tandem repeats (VNTRs) are a class of highly informative and widely dispersed genetic markers. Despite their wide application in biological science, little is known about their mutational mechanisms or population dynamics. The objective of this work was to investigate four summary measures of VNTR allele frequency distributions: number of alleles, number of modes, range in allele size and heterozygosity, using computer simulations of the one-step stepwise mutation model (SMM). We estimated these measures and their probability distributions for a wide range of mutation rates and compared the simulation results with predictions from analytical formulations of the one-step SMM. The average heterozygosity from the simulations agreed with the analytical expectation under the SMM. The average number of alleles, however, was larger in the simulations than the analytical expectation of the SMM. We then compared our simulation expectations with actual data reported in the literature. We used the sample size and observed heterozygosity to determine the expected value, 5th and 95th percentiles for the other three summary measures, allelic size range, number of modes and number of alleles. The loci analyzed were classified into three groups based on the size of the repeat unit: microsatellites (1-2 base pair (bp) repeat unit), short tandem repeats [(STR) 3-5 bp repeat unit], and minisatellites (15-70 bp repeat unit). In general, STR loci were most similar to the simulation results under the SMM for the three summary measures (number of alleles, number of modes and range in allele size), followed by the microsatellite loci and then by the minisatellite loci, which showed deviations in the direction of the infinite allele model (IAM). Based on these differences, we hypothesize that these three classes of loci are subject to different mutational forces.


Somatic neurofibromatosis type 1 (NF1) inactivation characterizes NF1-associated pilocytic astrocytoma.
Low-grade brain tumors (pilocytic astrocytomas) arising in the neurofibromatosis type 1 (NF1) inherited cancer predisposition syndrome are hypothesized to result from a combination of germline and acquired somatic NF1 tumor suppressor gene mutations. However, genetically engineered mice (GEM) in which mono-allelic germline Nf1 gene loss is coupled with bi-allelic somatic (glial progenitor cell) Nf1 gene inactivation develop brain tumors that do not fully recapitulate the neuropathological features of the human condition. These observations raise the intriguing possibility that, while loss of neurofibromin function is necessary for NF1-associated low-grade astrocytoma development, additional genetic changes may be required for full penetrance of the human brain tumor phenotype. To identify these potential cooperating genetic mutations, we performed whole-genome sequencing (WGS) analysis of three NF1-associated pilocytic astrocytoma (PA) tumors. We found that the mechanism of somatic NF1 loss was different in each tumor (frameshift mutation, loss of heterozygosity, and methylation). In addition, tumor purity analysis revealed that these tumors had a high proportion of stromal cells, such that only 50%-60% of cells in the tumor mass exhibited somatic NF1 loss. Importantly, we identified no additional recurrent pathogenic somatic mutations, supporting a model in which neuroglial progenitor cell NF1 loss is likely sufficient for PA formation in cooperation with a proper stromal environment.


Roles of the ether oxygen in hydration of tetrahydrofuran studied by IR, NMR, and DFT calculation methods.
We studied the concentration dependence of nu(C-H)'s in IR and (1)J(C,H) in NMR for binary water-tetrahydrofuran (THF) mixtures and found different trends for the two types of CH(2) groups in the five-membered ring. The changes of the nu(C-O) spectra showed that complexes of THF associated with water are formed, in which the number of water molecules increases with the water concentration. We suggested that hydration proceeds through the formation of 1:1, and 1:2 complexes of [THF:water] up to X(H(2)O) approximately 0.9, where X(H)((2))(O) is the mole fraction of the water in the mixtures. We carried out ab initio MO and DFT calculations to optimize the geometries of a THF dimer as a model of THF molecules in pure liquid, and 1:1 and 1:2 complexes of [THF:water] to simulate observed concentration dependence of nu(C-H)'s in IR and (1)J(C,H) in NMR. The changes of the calculated nu(C-H) spectra and (1)J(C,H) values for the optimized complexes are in agreement with those observed with varying X(H)((2))(O), supporting our proposal. From the vibrational and NBO analyses of the optimized complexes, the observed blue shift of nu(C-H)'s and the increase of (1)J(C,H) for the CH(2) groups neighboring to the ether oxygen were explained in terms of the changes in the stereoelectronic effect, resulting from HO-H...O< hydrogen bonding. The optimized 1:2-complex contains two weak C-H...OH(2) hydrogen bonds, and blue shift of nu(C-H)'s and increase of (1)J(C,H) were demonstrated from the same analyses of the complexes. This result of simulation also supports that the blue shift of nu(C-H)'s and increase of (1)J(C,H) observed for both the type of CH(2) groups at 0.6 X(H)((2))(O) < 0.9 are attributed to these interactions. On the basis of all these results, we propose that the formation of the 1:2-complex involving weak C-H...OH(2) hydrogen bonds is responsible dominantly for the hydrophobic hydration of THF.


Aberrant gyrification contributes to the link between gestational age and adult IQ after premature birth.
Gyrification is a hallmark of human brain development, starting in the second half of gestation in primary cortices, followed by unimodal and then transmodal associative cortices. Alterations in gyrification have been noted in premature-born newborns and children, suggesting abnormal cortical folding to be a permanent feature of prematurity. Furthermore, both gyrification and prematurity are tightly linked with cognitive performance, indicating a link between prematurity, gyrification, and cognitive performance. To investigate this triangular relation, we tested the following two hypotheses: (i) gyrification is aberrant in premature-born adults; and (ii) aberrant gyrification contributes to the impact of prematurity on adult cognitive performance. One hundred and one very premature-born adults (i.e. adults born before 32 weeks of gestation, and/or with birth weight <1500 g) and 111 mature-born adults were assessed by structural MRI and cognitive testing at 27 years of age. Gyrification was measured by local cortical absolute mean curvature (AMC), evaluated through structural MRI. Cognitive performance was assessed by the Wechsler Adult Intelligence Scale, full-scale IQ test. Two-sample t-tests, regression and mediation analyses were used to assess AMC group differences and the relation between AMC, birth-related variables, and full-scale IQ. Three key findings were identified. First, local AMC was widely increased in fronto-temporo-parietal primary and associative cortices of very premature-born adults. Increase of AMC was inversely associated with gestational age and birth weight and positively associated with medical complications at birth, respectively. Second, increased AMC of temporal associative cortices specifically contributed to the association between prematurity and reduced adult IQ (two-path mediation), indicating that aberrant gyrification of temporal associative cortices is critical for impaired cognitive performance after premature birth. Finally, further investigation of the relationship of gyrification between the early folding postcentral cortices and associative temporal cortices, folding later during neurodevelopment, revealed that the effect of gyrification abnormalities in associative temporal cortices on adult IQ is influenced itself by gyrification abnormalities occurring in the early folding postcentral cortices (three-path mediation). These results indicate that gyrification development across cortical areas in the brain conveys prematurity effects on adult IQ. Overall, these results provide evidence that premature birth leads to permanently aberrant gyrification patterns suggesting an altered neurodevelopmental trajectory. Statistical mediation modelling suggests that both aberrant gyrification itself as well as its propagation across the cortex express aspects of impaired neurodevelopment after premature birth and lead to reduced cognitive performance in adulthood. Thus, markers of gyrification appear as potential candidates for prognosis and treatment of prematurity effects.


Classification and nomenclature of the superfamily of short-chain dehydrogenases/reductases (SDRs).
The short-chain dehydrogenases/reductases (SDRs) constitute one of the largest protein superfamilies known today. The members are distantly related with typically 20-30% residue identity in pair-wise comparisons. Still, all hitherto structurally known SDRs present a common three-dimensional structure consisting of a Rossmann fold with a parallel beta sheet flanked by three helices on each side. Using hidden Markov models (HMMs), we have developed a semi-automated subclassification system for this huge family. Currently, 75% of all SDR forms have been assigned to one of the 464 families totalling 122,940 proteins. There are 47 human SDR families, corresponding to 75 genes. Most human SDR families (35 families) have only one gene, while 12 have between 2 and 8 genes. For more than half of the human SDR families, the three-dimensional fold is known. The number of SDR members increases considerably every year, but the number of SDR families now starts to converge. The classification method has paved the ground for a sustainable and expandable nomenclature system. Information on the SDR superfamily is continuously updated at http://sdr-enzymes.org/.


Changes in the patterns of care of central nervous system tumours among 16-24 year olds and the effect on survival in Yorkshire between 1990 and 2009.
There is a paucity of work documenting the influence of patterns of care on survival for teenagers and young adults with primary central nervous system tumours. Therefore, the aim of this study was to undertake a detailed assessment examining any changes in the patterns of care over time and how these related to survival outcomes for 16-24 year olds diagnosed with a primary central nervous system tumour between 1990 and 2009. We used high-quality data from one population-based cancer registry in Yorkshire, UK to describe primary central nervous system tumours in teenagers and young adults (16-24 years) diagnosed between 1990 and 2009. The Birch classification scheme was used to identify differences by tumour subgroup. Incidence, patterns of care and survival trends were described using Poisson and Cox regression. There were 163 cases comprising 98 astrocytomas, 17 'other gliomas', 14 ependymomas, 11 medulloblastomas and 23 'other intracranial and intraspinal neoplasms' yielding an overall incidence of 18.1 million person-years. Care varied significantly over time and by principal treatment centre (Leeds 77%, Hull 23%), co-ordinating specialty (neurosurgery 53%, clinical oncology 22%, paediatrics 17%, other adult services 8%) and treatment received. Cox regression showed no significant difference in survival by age, gender, treatment centre, level of deprivation, year of diagnosis or co-ordinating specialty, but a significant difference by tumour grade and diagnostic group. Survival improved for all diagnostic groups except astrocytoma, although only the medulloblastoma group showed a significant change over time. The lack of any significant improvement in survival over time in most diagnostic groups warrants further investigation and provides justification for a more collaborative regional approach to the care of central nervous system tumours, perhaps through the development of regional guidelines for this unique population. More detailed analysis of relapse patterns and prediagnostic symptoms would also be informative for this cohort.


Metabolic flux analyses to assess the differentiation of adult cardiac progenitors after fatty acid supplementation.
Myocardial infarction is the most prevalent of cardiovascular diseases and pharmacological interventions do not lead to restoration of the lost cardiomyocytes. Despite extensive stem cell therapy studies, clinical trials using cardiac progenitor cells have shown moderate results. Furthermore, differentiation of endogenous progenitors to mature cardiomyocytes is rarely reported. A metabolic switch from glucose to fatty acid oxidation occurs during cardiac development and cardiomyocyte maturation, however in vitro differentiation protocols do not consider the lack of fatty acids in cell culture media. The aim of this study was to assess the effect of this metabolic switch on control and differentiated adult cardiac progenitors, by fatty acid supplementation. Addition of oleic acid stimulated the peroxisome proliferator-activated receptor alpha pathway and led to maturation of the cardiac progenitors, both before and after transforming growth factor-beta 1 differentiation. Addition of oleic acid following differentiation increased expression of myosin heavy chain 7 and connexin 43. Also, total glycolytic metabolism increased, as did mitochondrial membrane potential and glucose and fatty acid transporter expression. This work provides new insights into the importance of fatty acids, and of peroxisome proliferator-activated receptor alpha, in cardiac progenitor differentiation. Harnessing the oxidative metabolic switch induced maturation of differentiated endogenous stem cells. (200 words).


Assessing the potential success of cystic fibrosis carrier screening: lessons learned from Tay-Sachs disease and beta-thalassemia.
The objective of this study was to identify factors involved in the success of 2 well-established population-based carrier screening programs - Tay-Sachs disease (TSD) in Ashkenazi Jews and beta-thalassemia in Sardinia and Cyprus - and to assess the potential for success of a population-based cystic fibrosis (CF) carrier screening strategy using these factors. We performed a literature review and key informant interviews. Factors involved in the success of TSD and beta-thalassemia carrier screening programs include disease characteristics (well-defined population at risk, severe disease with predictable course, availability of effective treatment), test characteristics (high sensitivity, straightforward interpretation of results), and community characteristics (involvement of community, support of families and advocacy groups, consensus in favor of avoiding affected births). Current CF screening strategies include few of the factors listed above. Unlike TSD and beta-thalassemia, the purpose of current CF carrier screening strategies is informed reproductive decision-making, without an explicit goal of reducing disease incidence. When compared to TSD and beta-thalassemia, CF is a less favorable candidate for population-based carrier screening. Because of its different purpose, CF carrier screening will require different measures of success than those used for TSD and beta-thalassemia carrier screening, and a consensus on the value or success of CF carrier screening may be difficult to achieve.


Residents' perceptions of water quality improvements following remediation work in the Pymme's Brook catchment, north London, UK.
Residents' perceptions of water quality change following remediation work in the upper Pymme's Brook catchment (north London) were elicited by questionnaire and compared with monitored changes in Escherichia coli count and BMWP (The Biological Monitoring Working Party (BMWP)) score. The wider usefulness of consumer perception surveys was then discussed. Monthly data collected between 1990 and 1996 shows that both E. coli count and BMWP score improved following flushing of the foul sewerage system in 1992, but that only E. coli count improved following the subsequent completion of large-scale remedial engineering works. Local residents were surveyed regarding their awareness of the scheme, and the causes of pollution, together with their perceptions as to the effects of the engineering works and of the resulting water quality improvements. Most respondents selected and ranked indicators in a way that suggested they had an awareness of the significance of various indicators of pollution severity. Following completion of the remediation scheme, residents perceived the watercourse to contain less rubbish and sewage fungus, and to have an improved colour and smell, which corresponds favourably to the monitored improvements. However, respondents' perceptions were found to vary when the study population was sub-divided using a range of parameters. For instance, frequent observers of the brook were most likely to correctly identify sewage as the main form of pollution. These divergent perceptions suggest that there may be considerable difficulties when perception surveys are used to quantify 'benefits' following environmental improvement programmes. Nevertheless, the survey was clearly beneficial in enhancing residents' awareness of their environment and the role of their voice in its management.


Absence of neurocognitive effect of hepatitis C infection in HIV-coinfected people.
To investigate the effect of hepatitis C virus (HCV) on neurocognitive performance in chronically HIV-infected patients enrolled in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study. A total of 1,582 participants in CHARTER who were tested for HCV antibody underwent neurocognitive testing; serum HCV RNA was available for 346 seropositive patients. Neurocognitive performance was compared in 408 HCV-seropositive and 1,174 HCV-seronegative participants and in a subset of 160 seropositive and 707 seronegative participants without serious comorbid neurologic conditions that might impair neurocognitive performance, using linear regression and taking into account HIV-associated and demographic factors (including IV drug use) and liver function. Neurocognitive performance characterized by global deficit scores and the proportion of individuals who were impaired were the same in the HCV-seropositive and HCV-seronegative groups. In univariable analyses in the entire sample, only verbal domain scores showed small statistically different superior performance in the HCV+ group that was not evident in multivariable analysis. In the subgroup without significant comorbidities, scores in all 7 domains of neurocognitive functioning did not differ by HCV serostatus. Among the HCV-seropositive participants, there was no association between neurocognitive performance and serum HCV RNA concentration. In HIV-infected patients, HCV coinfection does not contribute to neurocognitive impairment, at least in the absence of substantial HCV-associated liver damage, which was not evident in our cohort.


Pointing and tracking errors due to localized distortion induced by a transmission-type antenna in intersatellite laser communications.
A truncated ellipse Gaussian model to express localized distortion is developed to a transmission-type optical antenna, based on which the effects of localized deformation on pointing and tracking errors are researched. It is shown that localized distortion has the greatest influence on pointing and tracking errors when distortion deepness h approximately 0.8 lambda, which does not depend on other distortion parameters. To reduce the impact of localized deformation on pointing and tracking errors, the machining precision of the objective lens of the transmission-type antenna should be much better than 0.8 lambda. The requirement of the machining precision for lenses is lower than that for mirrors. The maxima of pointing and tracking errors due to the localized distortion with different radii are given. We hope the results can be used in the design of intersatellite optical communication systems.


The sucrose-trehalose 6-phosphate (Tre6P) nexus: specificity and mechanisms of sucrose signalling by Tre6P.
Trehalose 6-phosphate (Tre6P), the intermediate of trehalose biosynthesis, has a profound influence on plant metabolism, growth, and development. It has been proposed that Tre6P acts as a signal of sugar availability and is possibly specific for sucrose status. Short-term sugar-feeding experiments were carried out with carbon-starved Arabidopsis thaliana seedlings grown in axenic shaking liquid cultures. Tre6P increased when seedlings were exogenously supplied with sucrose, or with hexoses that can be metabolized to sucrose, such as glucose and fructose. Conditional correlation analysis and inhibitor experiments indicated that the hexose-induced increase in Tre6P was an indirect response dependent on conversion of the hexose sugars to sucrose. Tre6P content was affected by changes in nitrogen status, but this response was also attributable to parallel changes in sucrose. The sucrose-induced rise in Tre6P was unaffected by cordycepin but almost completely blocked by cycloheximide, indicating that de novo protein synthesis is necessary for the response. There was a strong correlation between Tre6P and sucrose even in lines that constitutively express heterologous trehalose-phosphate synthase or trehalose-phosphate phosphatase, although the Tre6P:sucrose ratio was shifted higher or lower, respectively. It is proposed that the Tre6P:sucrose ratio is a critical parameter for the plant and forms part of a homeostatic mechanism to maintain sucrose levels within a range that is appropriate for the cell type and developmental stage of the plant.


Effects of an aminomethacrylate on epithelial cell lipid metabolism.
Methacrylates can affect cell functions by surfactant-like effects or by altering cell lipid composition. Dimethylaminoethyl methacrylate (DMAEMA), an activator widely used in visible-light polymerized dental resins has been shown to elute readily into aqueous environments. The current study examined the metabolism of this material by oral epithelial cells (HCP) and its subsequent effects on cell lipids. Cells were plated in culture medium, then exposed to DMAEMA in the presence of 14C-acetate, a precursor which labeled the cell lipids. Other cultures were prelabeled with radioisotope, then exposed to DMAEMA. After incubation, the cell lipids were extracted and separated by TLC. Radioactive lipids were located and quantitated. Exposure of the cells to DMAEMA resulted in decreased synthesis of cholesterol with a concomitant increase in sterol precursors. Cholesterol esters and triacylglycerides also increased. Among the polar lipids, phosphatidyl choline (PC) and phosphatidyl ethanolamine (PE) decreased in response to DMAEMA. However, dimethylphosphatidyl ethanolamine (DMPE), a precursor of PC not detectable in control cultures, accumulated to a significant extent in cells exposed to DMAEMA. Furthermore, changes in PC and DMPE levels persisted in the cells for at least 48 h after removal of the DMAEMA. The results indicate that DMAEMA produces alterations in the relative amounts of several cellular neutral and polar lipids. Such alterations, especially of the normal phospholipid composition, along with an alteration in cellular cholesterol, could result in altered membrane-associated cell functions.


Versican is upregulated in circulating monocytes in patients with systemic sclerosis and amplifies a CCL2-mediated pathogenic loop.
Altered phenotypes of circulating monocytes of patients with systemic sclerosis (SSc) have been reported, but the role of these alterations in the pathogenesis of SSc remains unclear. This study was undertaken to identify molecules that are preferentially expressed by SSc monocytes, and to investigate the roles of these molecules in the pathogenic process of SSc. We analyzed circulating CD14⁺ monocytes isolated from 36 patients with SSc and 32 healthy control subjects. The monocytes' gene expression profiles were assessed by Oligo GEArray (SABiosciences, Frederic, MA, USA) and semiquantitative or quantitative PCR; their protein expression was evaluated in culture supernatants of unstimulated monocytes by immunoblotting or ELISA, and by immunocytostaining. Monocyte chemoattractant activity of CCL2 was assessed in a TransWell system (Corning Incorporated, Corning, NY, USA) in the presence or absence of chondroitin sulfate (CS). A step-wise approach to profiling gene expression identified that versican and CCL2 were upregulated in SSc monocytes. Subsequent analysis of proteins expressed in monocyte culture supernatants confirmed enhanced production of versican and CCL2 in SSc monocytes compared with control monocytes. CCL2 bound to CS chains of versican and colocalized with versican in the monocytes' Golgi apparatus. Finally, CCL2 had a greater ability to mediate monocyte migration when bound to CS chains, because this binding provided efficient formation of CCL2 gradients and protection from protease attack. Circulating monocytes with elevated versican and CCL2 levels may contribute to the fibrotic process in a subset of SSc patients by amplifying a positive feedback loop consisting of versican, CCL2, and the influx of monocytes.


BCL2-mediated tumorigenicity of a human T-lymphoid cell line: synergy with MYC and inhibition by BCL2 antisense.
A gene-transfer approach was used to explore the function of the BCL2 (B-cell lymphoma/leukemia 2) gene in a human T-cell line, Jurkat. Though stable introduction of a BCL2 expression plasmid into Jurkat T cells was by itself insufficient, the combined transfer of BCL2 and MYC genes markedly enhanced the tumorigenicity of these cells in athymic mice. Moreover, a BCL2 antisense expression plasmid ablated tumor formation by Jurkat cells, providing further evidence that this oncogene contributes to the regulation of the in vivo growth of these human T lymphocytes. In addition to their influence on tumor formation, BCL2 sense and antisense expression plasmids increased and decreased, respectively, the in vitro survival of Jurkat T cells in serum-free medium. These observations extend to T cells the finding of synergy of BCL2 with MYC previously reported for B cells and provide evidence that BCL2 can regulate the growth of human T cells.


Αlpha-Synuclein as a Mediator in the Interplay between Aging and Parkinson's Disease.
Accumulation and misfolding of the alpha-synuclein protein are core mechanisms in the pathogenesis of Parkinson's disease. While the normal function of alpha-synuclein is mainly related to the control of vesicular neurotransmission, its pathogenic effects are linked to various cellular functions, which include mitochondrial activity, as well as proteasome and autophagic degradation of proteins. Remarkably, these functions are also affected when the renewal of macromolecules and organelles becomes impaired during the normal aging process. As aging is considered a major risk factor for Parkinson's disease, it is critical to explore its molecular and cellular implications in the context of the alpha-synuclein pathology. Here, we discuss similarities and differences between normal brain aging and Parkinson's disease, with a particular emphasis on the nigral dopaminergic neurons, which appear to be selectively vulnerable to the combined effects of alpha-synuclein and aging.


Delivery of pharmaceutical services at ward level in a teaching hospital.
Poor management of pharmaceuticals could lead to wastage of financial resources and poor services in the public sector. The main aim of the study was to investigate the quality of pharmaceutical services at ward level in a teaching hospital. The design of the study was descriptive. Three data collection instruments were designed and pilot-tested prior to the actual data collection. Two structured questionnaires were used to interview the sister-in-charge of each ward and the stock and drug controller at the pharmacy. A checklist for the management of pharmaceuticals was completed for each ward. Descriptive statistics were used to describe and summarise the data. Sisters-in-charge of 30 wards and the stock and drug controller at the pharmacy participated in the study. The relationship with the pharmacy was perceived to be average by 54% (n = 30) of the sisters-in-charge of the wards. Communication with the pharmacy was mainly by telephone and 57% of the sisters-in-charge mentioned that they experienced difficulties in conveying messages to the pharmacy. Ten of the wards received regular ward visits by a pharmacist. Expiry dates were checked by all wards but at different intervals. The majority of the wards (90%) used patient cards, which refer to prescription charts, for stock control and ordering from the pharmacy. Fridge temperatures were checked and charted on a daily basis by 30% of the wards. Written standard operating procedures (SOPs) were used by the pharmacy for issuing ward stock. Although 83% of the wards indicated that they used SOPs, evidence of written SOPs was not available. The results indicated that the management of pharmaceutical services at ward level could be improved. Implementation of appropriate communication systems will enhance cooperation between the pharmacy and the wards. A uniform ward stock control system, either by computer or stock cards, should be introduced. Regular ward visits by a pharmacist to oversee ward stock management are recommended. Standard operating procedures for use in the wards should be developed and implemented.


Decreased function of survival motor neuron protein impairs endocytic pathways.
Spinal muscular atrophy (SMA) is caused by depletion of the ubiquitously expressed survival motor neuron (SMN) protein, with 1 in 40 Caucasians being heterozygous for a disease allele. SMN is critical for the assembly of numerous ribonucleoprotein complexes, yet it is still unclear how reduced SMN levels affect motor neuron function. Here, we examined the impact of SMN depletion in Caenorhabditis elegans and found that decreased function of the SMN ortholog SMN-1 perturbed endocytic pathways at motor neuron synapses and in other tissues. Diminished SMN-1 levels caused defects in C. elegans neuromuscular function, and smn-1 genetic interactions were consistent with an endocytic defect. Changes were observed in synaptic endocytic proteins when SMN-1 levels decreased. At the ultrastructural level, defects were observed in endosomal compartments, including significantly fewer docked synaptic vesicles. Finally, endocytosis-dependent infection by JC polyomavirus (JCPyV) was reduced in human cells with decreased SMN levels. Collectively, these results demonstrate for the first time, to our knowledge, that SMN depletion causes defects in endosomal trafficking that impair synaptic function, even in the absence of motor neuron cell death.


Comorbidity and its relevance on general hospital based mortality in major depressive disorder: a naturalistic 12-year follow-up in general hospital admissions.
Major depressive disorder (MDD) is associated with physical comorbidity, but the risk factors of general hospital-based mortality are unclear. Consequently, we investigated whether the burden of comorbidity and its relevance on in-hospital death differs between patients with and without MDD in a 12-year follow-up in general hospital admissions. During 1 January 2000 and 30 June 2012, 9604 MDD patients were admitted to three General Manchester Hospitals. All comorbidities with a prevalence ≥1% were compared with those of 96,040 age-gender matched hospital controls. Risk factors of in-hospital death were identified using multivariate logistic regression analyses. Crude hospital-based mortality rates within the period under observation were 997/9604 (10.4%) in MDD patients and 8495/96,040 (8.8%) in controls. MDD patients compared to controls had a substantial higher burden of comorbidity. The highest comorbidities included hypertension, asthma, and anxiety disorders. Subsequently, twenty-six other diseases were disproportionally increased, many of them linked to chronic lung diseases and to diabetes. In deceased MDD patients, chronic obstructive pulmonary disease and type-2 diabetes mellitus were the most common comorbidities, contributing to 18.6% and 17.1% of deaths. Furthermore, fifteen physical diseases contributed to in-hospital death in the MDD population. However, there were no significant differences in their impact on mortality compared to controls in multivariate logistic regression analyses. Thus in one of the largest samples of MDD patients in general hospitals, MDD patients have a substantial higher burden of comorbidity compared to controls, but they succumb to the same physical diseases as their age-gender matched peers without MDD.


Are seizures predictors of mortality in critically ill patients in the intensive care unit (ICU)?
This study aimed to determine if seizures in critically ill patients are predictive of in-hospital mortality. Patients above the age of 55 who underwent continuous electroencephalogram (cEEG) monitoring between 2015 and 2018 at the Hackensack Meridian Health and JFK Neuroscience Institute were included in the present study. Patients were subdivided into those with and without seizures. Age, sex, seizure types, CNS disorders, and other associated comorbidities were collected by chart review. After descriptive analysis, we used multiple logistic regression analyses to evaluate if seizures and mortality were associated. P-values less than 0.05 were considered statistically significant. One hundred and one critically ill patients (62.4% female) were included in this study. Sixty-six (65.3%) were between 55 and 75 years of age, while 35 (34.7%) were above 75 years of age. Most patients (n = 31, 83.8%) had focal-onset seizures, and 10 had nonconvulsive status epilepticus (NCSE). Twelve (11.9%) patients with seizures did not survive. However, seizures were not independently associated with mortality in either unadjusted (OR 1.13, CI 0.47-2.72, p = 0.773) or adjusted (OR 1.20, CI 0.35-4.05, p = 0.760) regression models. Secondary predictors of mortality included mechanical ventilation (OR 5.36, CI 1.69-16.96, p = 0.001) and acute ischemic stroke (OR 2.77, CI 1.08-7.09, p = 0.034). Seizures did not predict in-hospital mortality in critically ill patients. Larger prospective studies are needed to confirm our current findings.


Gas-phase structure and reactivity of the keto tautomer of the deoxyguanosine radical cation.
Guanine radical cations are formed upon oxidation of DNA. Deoxyguanosine (dG) is used as a model, and the gas-phase infrared (IR) spectroscopic signature and gas-phase unimolecular and bimolecular chemistry of its radical cation, dG˙(+), A, which is formed via direct electrospray ionisation (ESI/MS) of a methanolic solution of Cu(NO3)2 and dG, are examined. Quantum chemistry calculations have been carried out on 28 isomers and comparisons between their calculated IR spectra and the experimentally-measured spectra suggest that A exists as the ground-state keto tautomer. Collision-induced dissociation (CID) of A proceeds via cleavage of the glycosidic bond, while its ion–molecule reactions with amine bases occur via a number of pathways including hydrogen-atom abstraction, proton transfer and adduct formation. A hidden channel, involving isomerisation of the radical cation via adduct formation, is revealed through the use of two stages of CID, with the final stage of CID showing the loss of CH2O as a major fragmentation pathway from the reformed radical cation, dG˙(+). Quantum chemistry calculations on the unimolecular and bimolecular reactivity are also consistent with A being present as a ground-state keto tautomer.


Anaerobic bacteria in 118 patients with deep-space head and neck infections from the University Hospital of Maxillofacial Surgery, Sofia, Bulgaria.
The aim of this study was to assess the incidence and susceptibility to antibacterial agents of anaerobic strains in 118 patients with head and neck abscesses (31) and cellulitis (87). Odontogenic infection was the most common identified source, occurring in 73 (77.7%) of 94 patients. The incidence of anaerobes in abscesses and cellulitis was 71 and 75.9%, respectively, and that in patients before (31 patients) and after (87) the start of empirical treatment was 80.6 and 72.4%, respectively. The detection rates of anaerobes in patients with odontogenic and other sources of infection were 82.2 and 71.4%, respectively. In total, 174 anaerobic strains were found. The predominant bacteria were Prevotella (49 strains), Fusobacterium species (22), Actinomyces spp. (21), anaerobic cocci (20) and Eubacterium spp. (18). Bacteroides fragilis strains were isolated from 7 (5.9%) specimens. The detection rate of Fusobacterium strains from non-treated patients (32.2%) was higher than that from treated patients (13.8%). Resistance rates to clindamycin and metronidazole of Gram-negative anaerobes were 5.4 and 2.5%, respectively, and those of Gram-positive species were 4.5 and 58.3%, respectively. One Prevotella strain was intermediately susceptible to ampicillin/sulbactam. In conclusion, the start of empirical treatment could influence the frequency or rate of isolation of Fusobacterium species. The involvement of the Bacteroides fragilis group in some head and neck infections should be considered.


Integrated analyses of translatome and proteome identify the rules of translation selectivity in RPS14-deficient cells.
In ribosomopathies, the Diamond-Blackfan anemia (DBA) or 5q- syndrome, ribosomal protein (RP) genes are affected by mutation or deletion, resulting in bone marrow erythroid hypoplasia. Unbalanced production of ribosomal subunits leading to a limited ribosome cellular content regulates translation at the expense of the master erythroid transcription factor GATA1. In RPS14-deficient cells mimicking 5q- syndrome erythroid defects, we show that the transcript length, codon bias of the coding sequence (CDS) and 3'UTR (untranslated region) structure are the key determinants of translation. In these cells, short transcripts with a structured 3'UTR and high codon adaptation index (CAI) showed a decreased translation efficiency. Quantitative analysis of the whole proteome confirmed that the post-transcriptional changes depended on the transcript characteristics that governed the translation efficiency in conditions of low ribosome availability. In addition, proteins involved in normal erythroid differentiation share most determinants of translation selectivity. Our findings thus indicate that impaired erythroid maturation due to 5q- syndrome may proceed from a translational selectivity at the expense of the erythroid differentiation program, and suggest that an interplay between the CDS and UTR may regulate mRNA translation.


Visual symptoms and retinal straylight after laser peripheral iridotomy: the Zhongshan Angle-Closure Prevention Trial.
To assess the impact of laser peripheral iridotomy (LPI) on forward-scatter of light and subjective visual symptoms and to identify LPI parameters influencing these phenomena. Cohort study derived from a randomized trial, using an external control group. Chinese subjects initially aged 50 or older and 70 years or younger with bilateral narrow angles undergoing LPI in 1 eye selected at random, and age- and gender-matched controls. Eighteen months after laser, LPI-treated subjects underwent digital iris photography and photogrammetry to characterize the size and location of the LPI, Lens Opacity Classification System III cataract grading, and measurement of retinal straylight (C-Quant; OCULUS, Wetzlar, Germany) in the treated and untreated eyes and completed a visual symptoms questionnaire. Controls answered the questionnaire and underwent straylight measurement and (in a random one-sixth sample) cataract grading. Retinal straylight levels and subjective visual symptoms. Among 230 LPI-treated subjects (121 [58.8%] with LPI totally covered by the lid, 43 [19.8%] with LPI partly covered by the lid, 53 [24.4%] with LPI uncovered by the lid), 217 (94.3%) completed all testing, as did 250 (93.3%) of 268 controls. Age, gender, and prevalence of visual symptoms did not differ between treated subjects and controls, although nuclear (P<0.01) and cortical (P = 0.03) cataract were less common among controls. Neither presenting visual acuity nor straylight score differed between the treated and untreated eyes among all treated persons, nor among those (n = 96) with LPI partially or totally uncovered. Prevalence of subjective glare did not differ significantly between participants with totally covered LPI (6.61%; 95% confidence interval [CI], 3.39%-12.5%), partially covered LPI (11.6%; 95% CI, 5.07%-24.5%), or totally uncovered LPI (9.43%; 95% CI, 4.10%-10.3%). In regression models, only worse cortical cataract grade (P = 0.01) was associated significantly with straylight score, and no predictors were associated with subjective glare. None of the LPI size or location parameters were associated with straylight or subjective symptoms. These results suggests that LPI is safe regarding measures of straylight and visual symptoms. This randomized design provides strong evidence that treatment programs for narrow angles would be unlikely to result in important medium-term visual disability.


Age-specific fluoride exposure in drinking water and osteosarcoma (United States).
We explored age-specific and gender-specific effects of fluoride level in drinking water and the incidence of osteosarcoma. We used data from a matched case-control study conducted through 11 hospitals in the United States that included a complete residential history for each patient and type of drinking water (public, private well, bottled) used at each address. Our analysis was limited to cases less than 20 years old. We standardized fluoride exposure estimates based on CDC-recommended target levels that take climate into account. We categorized exposure into three groups (<30%, 30-99%, >99% of target) and used conditional logistic regression to estimate odds ratios. Analysis is based on 103 cases under the age of 20 and 215 matched controls. For males, the unadjusted odds ratios for higher exposures were greater than 1.0 at each exposure age, reaching a peak of 4.07 (95% CI 1.43, 11.56) at age 7 years for the highest exposure. Adjusting for potential confounders produced similar results with an adjusted odds ratio for males of 5.46 (95% CI 1.50, 19.90) at age 7 years. This association was not apparent among females. Our exploratory analysis found an association between fluoride exposure in drinking water during childhood and the incidence of osteosarcoma among males but not consistently among females. Further research is required to confirm or refute this observation.


Single-snippet analysis for detection of postspike effects.
Corticomotoneuronal cells (CMN), located predominantly in the primary motor cortex, project directly to alpha motoneuronal pools in the spinal cord. The effects of CMN spikes on motoneuronal excitability are traditionally characterized by visualizing postspike effects (PSEs) in spike-triggered averages (SpTA; Fetz, Cheney, & German, 1976; Fetz & Cheney, 1980; McKiernan, Marcario, Karrer, & Cheney, 1998) of electromyography (EMG) data. Poliakov and Schieber (1998) suggested a formal test, the multiple-fragment analysis (MFA), to automatically detect PSEs. However, MFA's performance was not statistically validated, and it is unclear under what conditions it is valid. This paper's contributions are a power study that validates the MFA; an alternative test, the single-snippet analysis (SSA), which has the same functionality as MFA but is easier to calculate and has better power in small samples; a simple bootstrap simulation to estimate SpTA baselines with simulation bands that help visualize potential PSEs; and a bootstrap adjustment to the MFA and SSA to correct for nonlinear SpTA baselines.


[Efficacy and perspective of application of preparation based on hydrogel and xerogel of methyl-silicic acid in patients with the intestinal malignancy].
There was studied the influence of medicinal preparations, created on the base of methylsiliconorganic matrix, on immediate and late follow-up result of treatment of more than 2000 patients with the digestive channel malignancy. High efficacy of application in complex of preoperative preparation of immobilized antibiotics and cytostatics, enterosorpent enterosgel for the purulent-inflammatory complications prophylaxis, lowering of bilirubin level in tumoral obturative jaundice, and in intraoperative usage for the tumor and metastases recurrences prophylaxis.


Epigenomic analysis of Alu repeats in human ependymomas.
Global loss of DNA methylation has been known for decades as an epigenomic aberration associated with carcinogenesis and cancer progression. Loss of DNA methylation affects predominantly repetitive elements, which encompass >50% of the CpG dinucleotides present in the human genome. Because of the lack of an effective approach, no studies have been conducted to reveal such genome-wide methylation changes at a single-base resolution. To precisely determine the CpG sites with methylation loss during progression of pediatric intracranial ependymomas, we exploited a high-throughput bisulfite sequencing approach that simultaneously generates methylation profiles for thousands of Alu elements and their flanking sequences. Comparison of the methylation profiles of normal and tumor tissues revealed that the methylation status of the majority of CpG sites adjacent to or within Alu repeats remain unaltered, while a small set of CpG sites gain or lose methylation in ependymomas. Compared to the CpG sites with stable methylation level between normal control and ependymomas, the differentially methylated CpG sites are enriched in the sequences with low CpG density in the flanking regions of Alu repeats, rather than within the Alu sequences themselves. In addition, the CpG sites that are hypermethylated in ependymomas are proximal to CpG islands, whereas those that are hypomethylated are overrepresented in intergenic regions. Lastly, aberrant methylation of several genomic loci was confirmed to be associated with the aggressive primary tumors and the relapsed ependymomas.


The EU approved antimalarial pyronaridine shows antitubercular activity and synergy with rifampicin, targeting RNA polymerase.
The search for compounds with biological activity for many diseases is turning increasingly to drug repurposing. In this study, we have focused on the European Union-approved antimalarial pyronaridine which was found to have in vitro activity against Mycobacterium tuberculosis (MIC 5 μg/mL). In macromolecular synthesis assays, pyronaridine resulted in a severe decrease in incorporation of 14C-uracil and 14C-leucine similar to the effect of rifampicin, a known inhibitor of M. tuberculosis RNA polymerase. Surprisingly, the co-administration of pyronaridine (2.5 μg/ml) and rifampicin resulted in in vitro synergy with an MIC 0.0019-0.0009 μg/mL. This was mirrored in a THP-1 macrophage infection model, with a 16-fold MIC reduction for rifampicin when the two compounds were co-administered versus rifampicin alone. Docking pyronaridine in M. tuberculosis RNA polymerase suggested the potential for it to bind outside of the RNA polymerase rifampicin binding pocket. Pyronaridine was also found to have activity against a M. tuberculosis clinical isolate resistant to rifampicin, and when combined with rifampicin (10% MIC) was able to inhibit M. tuberculosis RNA polymerase in vitro. All these findings, and in particular the synergistic behavior with the antitubercular rifampicin, inhibition of RNA polymerase in combination in vitro and its current use as a treatment for malaria, may suggest that pyronaridine could also be used as an adjunct for treatment against M. tuberculosis infection. Future studies will test potential for in vivo synergy, clinical utility and attempt to develop pyronaridine analogs with improved potency against M. tuberculosis RNA polymerase when combined with rifampicin.


Transcriptional regulation by a DNA-associated form of cyclin D1.
Besides its function as a cell cycle regulator, cyclin D1 interacts with transcription factors to regulate gene activation. In this study, we show that cyclin D1 is recruited to the p21waf1 promoter by a STAT3-NcoA complex. The association of cyclin D1 with DNA prevented the recruitment of the CBP histone acetylase and RNA polymerase II, leading to an inhibition of the p21waf1 gene. Confirming the transcriptional function of the protein, the expression of the p21waf1 gene was enhanced in cyclin D1-/- fibroblasts or upon siRNA-mediated down-regulation of the cyclin. Moreover, the STAT3-mediated activation of p21waf1 was also inhibited in breast cancer cells containing elevated levels of cyclin D1. Altogether, these results suggest that the transcriptional activities of cyclin D1 might play an important role in the regulation of cell-cycle regulatory genes and that these functions are probably involved in cell transformation.


Sweet bee venom pharmacopuncture for chemotherapy-induced peripheral neuropathy.
Chemotherapy-induced peripheral neuropathy (CIPN) is sensory and motor nerve damage to the peripheral nervous system caused by chemotherapeutic agents. It often causes pain and other varying degrees of neuropathic symptoms accompanied by functional limitations and reduced quality of life. Currently, there is no standard treatment protocol for the treatment of CIPN. In need of more research to develop new therapeutic options focusing on their safety, efficacy, and long-term sustained clinical effects, a pilot study of sweet bee venom pharmacopuncture (SBVP) for CIPN was conducted to build up preliminary efficacy data in the process of preparing for a future larger scale randomized controlled SBVP trial for CIPN. We conducted a prospective case series by analyzing the clinical observations made of CIPN patients treated with SBVP. A total of 11 eligible consecutive CIPN patients who visited East-West Cancer Center from June 1, 2010, to February 28, 2011, were treated with total of six SBVP treatments given within the 3-week period. The outcomes were measured using World Health Organization Common Toxicity Criteria for Peripheral neuropathy (WHO grading system), Patient Neurotoxicity Questionnaire (PNQ), Visual Analogue System (VAS), and Health-Related Quality of Life (HRQOL) collected at the baseline, post-second, fourth, and the final treatment. Patients were followed 3 weeks into no intervention to determine the sustained effects of pharmacopuncture. Both of the WHO CIPN grade and PNQ scores have shown a decrease in the level of neuropathy. VAS pain level has also shown a great decrease and improvement in patients' quality of life have also been detected though modest. Changes in WHO grade, VAS and Total HRQOL scores between the baseline and after the last treatment session were significant. Changes in WHO grade, Total PNQ, PNQ-sensory, VAS, Total HRQOL, and HRQOL-functional scores between the baseline and the 3-week follow-up were significant. The positive result of the study supports the potential value of conducting a fully powered trial to explore further efficacy of SBVP for CIPN. However a single positive result within this pilot study must be interpreted with caution.


Hepatic deletion of p110α and p85α results in insulin resistance despite sustained IRS1-associated phosphatidylinositol kinase activity.
Background: Class IA phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) is an integral mediator of insulin signaling. The p110 catalytic and p85 regulatory subunits of PI3K are the products of separate genes, and while they come together to make the active heterodimer, they have opposing roles in insulin signaling and action. Deletion of hepatic p110α results in an impaired insulin signal and severe insulin resistance, whereas deletion of hepatic p85α results in improved insulin sensitivity due to sustained levels of phosphatidylinositol (3,4,5)-trisphosphate. Here, we created mice with combined hepatic deletion of p110α and p85α (L-DKO) to study the impact on insulin signaling and whole body glucose homeostasis. Methods: Six-week old male flox control and L-DKO mice were studied over a period of 18 weeks, during which weight and glucose levels were monitored, and glucose tolerance tests, insulin tolerance test and pyruvate tolerance test were performed. Fasting insulin, insulin signaling mediators, PI3K activity and insulin receptor substrate (IRS)1-associated phosphatidylinositol kinase activity were examined at 10 weeks. Liver, muscle and white adipose tissue weight was recorded at 10 weeks and 25 weeks. Results: The L-DKO mice showed a blunted insulin signal downstream of PI3K, developed markedly impaired glucose tolerance, hyperinsulinemia and had decreased liver and adipose tissue weights. Surprisingly, however, these mice displayed normal hepatic glucose production, normal insulin tolerance, and intact IRS1-associated phosphatidylinositol kinase activity without compensatory upregulated signaling of other classes of PI3K. Conclusions: The data demonstrate an unexpectedly overall mild metabolic phenotype of the L-DKO mice, suggesting that lipid kinases other than PI3Ks might partially compensate for the loss of p110α/p85α by signaling through other nodes than Akt/Protein Kinase B.