Public Health Approaches and Barriers to Educating Providers about Hereditary Breast and Ovarian Cancer Syndrome.
The Michigan Department of Health and Human Services implemented and evaluated two initiatives designed to enhance provider knowledge of patients appropriate for breast and/or ovarian cancer genetic risk assessment and hereditary breast and ovarian cancer (HBOC) syndrome testing. The first initiative targeted select providers who had diagnosed patients meeting HBOC risk criteria. Specifically, the initiative used 2008-2009 state cancer registry data to identify all providers who had diagnosed breast cancers in women ≤50 years of age, male breast cancers, and ovarian cancers in four health systems with newly established cancer genetics clinics. Using a method coined bidirectional reporting (BDR), reports highlighting how many of these cases each provider had seen were generated and mailed. Reports on 475 cancers (9.5% of the 5005 cases statewide meeting criteria) were sent to 69 providers with information about how and why to refer such patients for genetic counseling. Providers who received a report were contacted to assess whether the reports increased awareness or resulted in action (genetic counseling/referral). Based on the few responses received, despite multiple attempts to contact, and attrition rate, it is not possible to ascertain the impact of this initiative on providers. However the project resulted in the MDHHS identifying which providers see the largest proportion of at-risk patients, creating an opportunity to target those providers with HBOC education efforts. The second initiative involved creating and broadly disseminating an online, interactive case-based educational module to increase awareness and referral decisions for HBOC using high- and low-risk patient scenarios. A total of 1835 unique users accessed the module in a one year. Collectively the users viewed topic pages 2724 times and the interactive case studies 1369 times. Point of care tools (fact sheets) were viewed 1624 times and downloaded 764 times. Satisfaction among the subset of users applying for continuing medical education credit was high. The online educational module had a much broader reach than the bidirectional reporting initiative but to a self-selected audience. Combining targeted and broad-based provider education efforts may be a better way to increase HBOC awareness in the target audience, starting with those providers seeing the largest proportion of patients at risk.


The Use of Caffeinated Substances by Surgeons for Cognitive Enhancement.
To investigate the use of coffee, caffeinated drinks, and caffeine tablets for pharmacological cognitive enhancement (CE) among surgeons. Surgeons have demanding workloads, and the resulting fatigue and concentration deficits can lead to medical errors. Some surgeons use substances that promote wakefulness to counteract these effects. A total of 3306 surgeons who attended 5 international conferences in 2011 were surveyed regarding their use of coffee, caffeinated drinks, and caffeine tablets for CE and potential factors derived from professional and private life using an anonymous self-report questionnaire. In this study, we were only interested in surgeons working in hospitals; therefore, 951 questionnaires were statistically analyzed. The most prevalent reason for using caffeine of any kind was to reduce fatigue (54.3%). Further prevalent reasons are working the night shift (32.2%) and overly long and excessive work hours (31.7%). Lifetime, past-year, past-month, and past-week prevalence was 66.8%, 61.9%, 56.9%, and 50.5%, for coffee use; 24.2%, 15.4%, 9.9%, and 6.1%, for caffeinated drinks; and 12.6%, 5.9%, 4.7%, and 3.8%, respectively, for caffeine tablets. Caffeine use was associated with lower age, male sex, divorced marital status, living with children, lack of satisfaction with professional status, pressure to perform in private life, and pressure perceived to be harmful to one's own health. Surgeons often use caffeinated substances to cope with fatigue and long working hours. Coffee use was more prevalent than the use of caffeinated drinks and caffeine tablets.


Src42A-dependent polarized cell shape changes mediate epithelial tube elongation in Drosophila.
Although many organ functions rely on epithelial tubes with correct dimensions, mechanisms underlying tube size control are poorly understood. We analyse the cellular mechanism of tracheal tube elongation in Drosophila, and describe an essential role of the conserved tyrosine kinase Src42A in this process. We show that Src42A is required for polarized cell shape changes and cell rearrangements that mediate tube elongation. In contrast, diametric expansion is controlled by apical secretion independently of Src42A. Constitutive activation of Src42A induces axial cell stretching and tracheal overelongation, indicating that Src42A acts instructively in this process. We propose that Src42A-dependent recycling of E-Cadherin at adherens junctions is limiting for cell shape changes and rearrangements in the axial dimension of the tube. Thus, we define distinct cellular processes that independently control axial and diametric expansion of a cylindrical epithelium in a developing organ. Whereas exocytosis-dependent membrane growth drives circumferential tube expansion, Src42A is required to orient membrane growth in the axial dimension of the tube.


Dynamic silencing of somatic L1 retrotransposon insertions reflects the developmental and cellular contexts of their genomic integration.
The ongoing mobilization of mammalian transposable elements (TEs) contributes to natural genetic variation. To survey the epigenetic control and expression of reporter genes inserted by L1 retrotransposition in diverse cellular and genomic contexts, we engineered highly sensitive, real-time L1 retrotransposon reporter constructs. Here we describe different patterns of expression and epigenetic controls of newly inserted sequences retrotransposed by L1 in various somatic cells and tissues including cultured human cancer cells, mouse embryonic stem cells, and tissues of pseudofounder transgenic mice and their progeny. In cancer cell lines, the newly inserted sequences typically underwent rapid transcriptional gene silencing, but they lacked cytosine methylation even after many cell divisions. L1 reporter expression was reversible and oscillated frequently. Silenced or variegated reporter expression was strongly and uniformly reactivated by treatment with inhibitors of histone deacetylation, revealing the mechanism for their silencing. By contrast, de novo integrants retrotransposed by L1 in pluripotent mouse embryonic stem (ES) cells underwent rapid silencing by dense cytosine methylation. Similarly, de novo cytosine methylation also was identified at new integrants when studied in several distinct somatic tissues of adult founder mice. Pre-existing L1 elements in cultured human cancer cells were stably silenced by dense cytosine methylation, whereas their transcription modestly increased when cytosine methylation was experimentally reduced in cells lacking DNA methyltransferases DNMT1 and DNMT3b. As a control, reporter genes mobilized by piggyBac (PB), a DNA transposon, revealed relatively stable and robust expression without apparent silencing in both cultured cancer cells and ES cells. We hypothesize that the de novo methylation marks at newly inserted sequences retrotransposed by L1 in early pre-implantation development are maintained or re-established in adult somatic tissues. By contrast, histone deacetylation reversibly silences L1 reporter insertions that had mobilized at later timepoints in somatic development and differentiation, e.g., in cancer cell lines. We conclude that the cellular contexts of L1 retrotransposition can determine expression or silencing of newly integrated sequences. We propose a model whereby reporter expression from somatic TE insertions reflects the timing, molecular mechanism, epigenetic controls and the genomic, cellular and developmental contexts of their integration.


Chronic D-amphetamine administered from childhood to adulthood dose-dependently increases the survival of new neurons in the hippocampus of male C57BL/6J mice.
Adderall is widely prescribed for attention deficit hyperactivity disorder (ADHD) though long term neurological effects of the main ingredient d-amphetamine are not well understood. The purpose of this study was to examine effects of clinically prescribed doses of d-amphetamine and one abuse dose administered from childhood to adulthood on adult hippocampal neurogenesis and activation of the granule layer of the dentate gyrus. Beginning in early adolescence (age 28 days) to adulthood (age 71), male C57BL/6J mice were administered twice daily i.p. injections of vehicle, 0.25, 0.5 or 2mg/kg d-amphetamine. Locomotor activity was measured in home cages by video tracking. At age 53-56, mice received bromodeoxyuridine (BrdU) injections to label dividing cells. Immunohistochemical detection of BrdU, neuronal nuclear protein (NeuN), doublecortin (DCX) and Ki67 was used to measure neurogenesis and cell proliferation at age 71. ΔFosB was measured as an indicator of repeated neuronal activation. An additional cohort of mice was treated similarly except euthanized at age 58 to measure activation of granule neurons from d-amphetamine (by detection of c-Fos) and cell proliferation (Ki67) at a time when the fate of BrdU cells would have been determined in the first cohort. d-Amphetamine dose-dependently increased survival and differentiation of BrdU cells into neurons and increased number of DCX cells without affecting the number of Ki67 cells. Low doses of d-amphetamine decreased c-Fos and ΔFosB in the granule layer. Only the high dose induced substantial locomotor stimulation and sensitization. Results suggest both therapeutic and abuse doses of d-amphetamine increase the number of new neurons in the hippocampus when administered from adolescence to adulthood by increasing survival and differentiation of cells into neurons not by increasing progenitor cell proliferation. Mechanisms for amphetamine-induced neurogenesis are unknown but appear activity independent. Results suggest part of the beneficial effects of therapeutic doses of d-amphetamine for ADHD could be via increased hippocampal neurogenesis.


Dietary consumption of advanced glycation end products and pancreatic cancer in the prospective NIH-AARP Diet and Health Study.
Advanced glycation end products (AGEs) are a heterogeneous group of compounds present in uncooked foods as well as in foods cooked at high temperatures. AGEs have been associated with insulin resistance, oxidative stress, and chronic inflammation in patients with diabetes. Dietary AGEs are an important contributor to the AGE pool in the body. N(ϵ)-(carboxymethyl)lysine (CML) AGE is one of the major biologically and chemically well-characterized AGE markers. The consumption of red meat, which is CML-AGE rich, has been positively associated with pancreatic cancer in men. With the use of a published food CML-AGE database, we estimated the consumption of CML AGE in the prospective NIH-AARP Diet and Health Study and evaluated the association between CML-AGE consumption and pancreatic cancer and the mediating effect of CML AGE on the association between red meat consumption and pancreatic cancer. Multivariate Cox proportional hazard regression models were used to estimate HRs and 95% CIs for pancreatic cancer. During an average of 10.5 y of follow-up, we identified 2193 pancreatic cancer cases (1407 men and 786 women) from 528,251 subjects. With the comparison of subjects in the fifth and the first quintiles of CML-AGE consumption, we observed increased pancreatic cancer risk in men (HR: 1.43; 95% CI: 1.06, 1.93, P-trend = 0.003) but not women (HR: 1.14; 95% CI: 0.76, 1.72, P-trend = 0.42). Men in the highest quintile of red meat consumption had higher risk of pancreatic cancer (HR: 1.35; 95% CI: 1.07, 1.70), which attenuated after adjustment for CML-AGE consumption (HR: 1.20; 95% CI: 0.95, 1.53). Dietary CML-AGE consumption was associated with modestly increased risk of pancreatic cancer in men and may partially explain the positive association between red meat and pancreatic cancer.


Flexible prototype thermoelectric devices based on Ag₂Te and PEDOT:PSS coated nylon fibre.
p- and n-type Ag₂Te nanocrystals are coated separately onto nylon fibres to create flexible composites. A prototype thermoelectric device made using such fibres produces ∼0.8 nW in a 20 K temperature difference. This is improved to over 5 nW by using a conducting polymer as the p-type material.


Bayesian nonparametric inference on quantile residual life function: Application to breast cancer data.
There is often an interest in estimating a residual life function as a summary measure of survival data. For ease in presentation of the potential therapeutic effect of a new drug, investigators may summarize survival data in terms of the remaining life years of patients. Under heavy right censoring, however, some reasonably high quantiles (e.g., median) of a residual lifetime distribution cannot be always estimated via a popular nonparametric approach on the basis of the Kaplan-Meier estimator. To overcome the difficulties in dealing with heavily censored survival data, this paper develops a Bayesian nonparametric approach that takes advantage of a fully model-based but highly flexible probabilistic framework. We use a Dirichlet process mixture of Weibull distributions to avoid strong parametric assumptions on the unknown failure time distribution, making it possible to estimate any quantile residual life function under heavy censoring. Posterior computation through Markov chain Monte Carlo is straightforward and efficient because of conjugacy properties and partial collapse. We illustrate the proposed methods by using both simulated data and heavily censored survival data from a recent breast cancer clinical trial conducted by the National Surgical Adjuvant Breast and Bowel Project.


Adiposity gain during childhood, ACE I/D polymorphisms and metabolic outcomes.
We aimed to (i) determine the relative importance of childhood gain in upper body adiposity for insulin resistance (IR) and triglyceridemia (TG); (ii) examine whether the associations between adiposity and metabolic indices were more evident in those with the ACE DD genotype. We examined a birth cohort study of 292 children with measures in the neonatal period (day 4) including subscapular and triceps skinfolds; repeat skinfold measures at age 8, cardiorespiratory (CR) fitness, IR by the homeostasis model assessment (HOMA) equation (HOMA-IR) and serum triglyceride (TG) concentrations and measures of ACE I/D gene variants. A multiple linear regression analysis incorporating a life course approach was undertaken. Childhood gain in upper body adiposity was positively associated with HOMA-IR and TG independently of neonatal skinfolds (P < or = 0.02). The magnitude of these associations was higher among those of the ACE DD genotype. For example, subscapular skinfold gain was not strongly associated with HOMA-IR or TG among those with II or ID genotype (b = 0.03, P = 0.05; b = 0.02, P = 0.18 respectively) but was positively associated among those with the DD genotype (b = 0.11, P = 0.001; b = 0.08, P = 0.003); difference in effect P = 0.05; P = 0.01 respectively. Upper body fat accumulation during childhood was positively associated with HOMA-IR and TG independently of neonatal skinfolds. Further, the stronger associations for those with the ACE DD genotype is consistent with randomised controlled trial findings that ACE inhibition is associated with a reduced risk of developing type 2 diabetes. Further work is required to confirm and extend these findings.


Commutability Assessment of Candidate Reference Materials for Pancreatic α-Amylase.
Measurement standardization of the catalytic concentration of α-amylase in serum is based on 3 pillars: the primary reference measurement procedure (PRMP), reference laboratories, and suitable certified reference materials (CRMs). Commutability is a prerequisite when using a CRM for calibration and trueness control of routine methods or for value transfer from the PRMP to end-user calibrators of routine methods through a calibration hierarchy. We performed a commutability study with 30 serum pools and 5 candidate reference materials (RMs) for pancreatic α-amylase using an automated version of the PRMP and 5 different routine methods. Four candidate RMs had an artificial matrix, each with a different composition, and 1 candidate RM was based on human serum. Data were analyzed according to a linear regression analysis with prediction interval as described in the Clinical and Laboratory Standards Institute guideline EP30-A and a difference in bias analysis as described in the recommendations of the IFCC Working Group on Commutability. The commutability profile of the 4 candidate RMs with an artificial matrix was variable. Only 1 candidate RM, with human serum albumin in the matrix, showed a good profile like that of the candidate RM based on serum. The comparison of both commutability assessment approaches indicated some differences because of inconclusive results for the difference in bias approach, suggesting a large uncertainty on the commutability assessment. A CRM for pancreatic amylase in an artificial matrix can be commutable for routine methods using the same substrate as the PRMP, but the matrix composition is crucial.


Energy metabolism in kidney of heat-acclimated hamsters.
Biochemical pathways which are involved in energy metabolism were examined in the kidney of heat-acclimated hamsters. It was found that heat acclimation caused 47% reduction in glucose-6-phosphatase (G1c-6-Pase) activity and 40% lower rate of gluconeogenesis. No changes were found in the activity of hexokinase, glucose-6-phosphate dehydrogenase, pyruvate kinase, lactic dehydrogenase, or in kidney glycogen content. Isolated kidney mitochondria of heat-acclimated hamsters utilized 15% less oxygen than that of controls, but no differences were found in the P/O ratio. Determination of the content of some cytochromes showed a significant reduction in cytochromes c + c1, but no difference was found in the content of cytochromes a, a3, and b. These results suggest that the kidney plays a role in the reduction of energy metabolism during the process of heat acclimation.


Molecular quantum cellular automata cell design trade-offs: latching vs. power dissipation.
The use of molecules to enact quantum cellular automata (QCA) cells has been proposed as a new way for performing electronic logic operations at sub-nm dimensions. A key question that arises concerns whether chemical or physical processes are to be exploited. The use of chemical reactions allows the state of a switch element to be latched in molecular form, making the output of a cell independent of its inputs, but costs energy to do the reaction. Alternatively, if purely electronic polarization is manipulated then no internal latching occurs, but no power is dissipated provided the fields from the inputs change slowly compared to the molecular response times. How these scenarios pan out is discussed by considering calculated properties of the 1,4-diallylbutane cation, a species often used as a paradigm for molecular electronic switching. Utilized are results from different calculation approaches that depict the ion either as a charge-localized mixed-valence compound functioning as a bistable switch, or else as an extremely polarizable molecule with a delocalized electronic structure. Practical schemes for using molecular cells in QCA and other devices emerge.


Single nucleotide polymorphisms (SNPs) distinguish Indian-origin and Chinese-origin rhesus macaques (Macaca mulatta).
Rhesus macaques serve a critical role in the study of human biomedical research. While both Indian and Chinese rhesus macaques are commonly used, genetic differences between these two subspecies affect aspects of their behavior and physiology, including response to simian immunodeficiency virus (SIV) infection. Single nucleotide polymorphisms (SNPs) can play an important role in both establishing ancestry and in identifying genes involved in complex diseases. We sequenced the 3' end of rhesus macaque genes in an effort to identify gene-based SNPs that could distinguish between Indian and Chinese rhesus macaques and aid in association analysis. We surveyed the 3' end of 94 genes in 20 rhesus macaque animals. The study included 10 animals each of Indian and Chinese ancestry. We identified a total of 661 SNPs, 457 of which appeared exclusively in one or the other population. Seventy-nine additional animals were genotyped at 44 of the population-exclusive SNPs. Of those, 38 SNPs were confirmed as being population-specific. This study demonstrates that the 3' end of genes is rich in sequence polymorphisms and is suitable for the efficient discovery of gene-linked SNPs. In addition, the results show that the genomic sequences of Indian and Chinese rhesus macaque are remarkably divergent, and include numerous population-specific SNPs. These ancestral SNPs could be used for the rapid scanning of rhesus macaques, both to establish animal ancestry and to identify gene alleles that may contribute to the phenotypic differences observed in these populations.


Geometrical tuning art for entirely subwavelength grating waveguide based integrated photonics circuits.
Subwavelength grating (SWG) waveguide is an intriguing alternative to conventional optical waveguides due to the extra degree of freedom it offers in tuning a few important waveguide properties, such as dispersion and refractive index. Devices based on SWG waveguides have demonstrated impressive performances compared to conventional waveguides. However, the high loss of SWG waveguide bends jeopardizes their applications in integrated photonic circuits. In this work, we propose a geometrical tuning art, which realizes a pre-distorted refractive index profile in SWG waveguide bends. The pre-distorted refractive index profile can effectively reduce the mode mismatch and radiation loss simultaneously, thus significantly reduce the bend loss. This geometry tuning art has been numerically optimized and experimentally demonstrated in present study. Through such tuning, the average insertion loss of a 5 μm SWG waveguide bend is reduced drastically from 5.43 dB to 1.10 dB per 90° bend for quasi-TE polarization. In the future, the proposed scheme will be utilized to enhance performance of a wide range of SWG waveguide based photonics devices.


Voltage sensors of the frog skeletal muscle membrane require calcium to function in excitation-contraction coupling.
1. Intramembrane charge movements and changes in intracellular Ca2+ concentration (Ca2+ transients) elicited by pulse depolarization were measured in frog fast twitch cut muscle fibres under voltage clamp. 2. Extracellular solutions with very low [Ca2+] and 2 mM-Mg2+ , shown in the previous paper to reduce Ca2+ release from the sarcoplasmic reticulum (SR), were found to cause two changes in charge movement: (a) a decrease (-12 nC/microF) in the charge that moves during depolarizing pulses from -90 to 0 mV, termed here 'charge 1'; (b) an increase (+7 nC/microF) in the charge moved by hyperpolarizing pulses from -90 to -180 mV, termed 'charge 2'. 3. The increase in charge moved by hyperpolarizing pulses was correlated (r = 0.64) with the decrease in charge moved by depolarizing pulses and both were correlated with the inhibition of Ca2+ release recorded in the same fibres. 4. The low Ca2+ solutions caused a shift to more negative voltages of the dependence relating charge movement and holding potential (VH). This shift is of similar magnitude (about 22 mV) and direction as the shift in the curve relating Ca2+ release flux to VH (previous paper). 5. In solutions with normal [Ca2+] a conditioning depolarization to 0 mV, of 2 s duration, placed 100 ms before a test pulse from -70 to 0 mV, reduced by 30% the amount of charge displaced by the test pulse. Conditioning pulses of 1 s or less caused potentiation of charge movement by up to 30%. 6. In low Ca2+ solutions, reduction of charge was observed at all durations of the conditioning pulse. The duration for half-inhibition was near 200 ms. 7. An extracellular solution with no metal cations caused a more radical inhibition than the low Ca2+ solutions that contained Mg2+. The inhibition of Ca2+ release was essentially complete (90-100%). The charge moved by a pulse to 0 mV was reduced by 20 nC/microF and the charge moved by a pulse to -170 mV increased 8 nC/microF. This shows that Mg2+ supports excitation-contraction (E-C) coupling to some extent. 8. A state model of the voltage sensor of E-C coupling explains qualitatively the observations in both papers.(ABSTRACT TRUNCATED AT 400 WORDS)


Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group.
The monoclonal gammopathies are a group of disorders associated with monoclonal proliferation of plasma cells. The characterization of specific entities is an area of difficulty in clinical practice. The International Myeloma Working Group has reviewed the criteria for diagnosis and classification with the aim of producing simple, easily used definitions based on routinely available investigations. In monoclonal gammopathy of undetermined significance (MGUS) or monoclonal gammopathy, unattributed/unassociated (MG[u]), the monoclonal protein is < 30 g/l and the bone marrow clonal cells < 10% with no evidence of multiple myeloma, other B-cell proliferative disorders or amyloidosis. In asymptomatic (smouldering) myeloma the M-protein is >/= 30 g/l and/or bone marrow clonal cells >/= 10% but no related organ or tissue impairment (ROTI)(end-organ damage), which is typically manifested by increased calcium, renal insufficiency, anaemia, or bone lesions (CRAB) attributed to the plasma cell proliferative process. Symptomatic myeloma requires evidence of ROTI. Non-secretory myeloma is characterized by the absence of an M-protein in the serum and urine, bone marrow plasmacytosis and ROTI. Solitary plasmacytoma of bone, extramedullary plasmacytoma and multiple solitary plasmacytomas (+/- recurrent) are also defined as distinct entities. The use of these criteria will facilitate comparison of therapeutic trial data. Evaluation of currently available prognostic factors may allow better definition of prognosis in multiple myeloma.


The influence of bottom boundary layer hydrodynamics on sediment focusing in a contaminated bay.
Understanding the dynamics and fate of particle bound contaminants is important for mitigating potential environmental, economic and health impacts linked to their presence. Vidy Bay, Lake Geneva (Switzerland), is contaminated due to the outfall and overflow from the wastewater treatment plant of the City of Lausanne. This study was designed to investigate the fate of particle-bound contaminants with the goal of providing a more complete picture of contaminant pathways within the bay and their potential spread to the main basin. This goal was achieved by investigating the sediment transport dynamics, using sediment traps and radionuclide tracers, and ascertaining how local bottom-boundary hydrodynamic conditions (temperature, turbidity, current velocity and direction) influence these dynamics. Results of the study indicated that sedimentation rates and lateral advections increased vertically with proximity to the lakebed and laterally with proximity to shore, indicating the presence of sediment focusing in the bay. Hydrodynamic measurements showed the persistent influence of a gyre within the bay, extending down to the lake bed, while just outside of the bay circulation was influenced by the seasonal patterns of the main basin. Calculated mean displacement distances in the bay indicated that suspended particles can travel ∼3 km per month, which is 1.7 times the width of the Vidy Bay gyre. This results in a residence time of approximately 21 days for suspended particles, which is much greater than previously modelled results. The calculated mobility Shield parameter never exceeded the threshold shear stress needed for resuspension in deeper parts of the bay. In such, increased lateral advections to the bay are not likely due to local resuspension but rather external particle sources, such as main basin or shallow, littoral resuspensions. These external sources coupled with an increased residence time and decreased current velocity within the bay are the precipitating factors in sediment focusing. While the spread of contaminants from the bay may occur through the transport of fine suspended sediments in shallower zones of the bay (<60 m) by longshore littoral currents, results suggest that particle-bound contaminants are likely to remain within the bay.


Low fructosamine and mortality - A long term follow-up of 215,011 non-diabetic subjects in the Swedish AMORIS study.
Both high and low fasting glucose has been associated with an increased mortality among individuals without diabetes. This J-shaped association has also been shown for HbA1c in relation to all-cause mortality. High fructosamine is associated with increased mortality. In this study we aim to evaluate if low fructosamine is also associated with increased mortality in non-diabetic subjects. We included 215,011 subjects from the AMORIS cohort undergoing occupational health screening or primary care in Stockholm, Sweden. Cause specific mortality was obtained from the Swedish Cause-of-Death Register by record linkage. Hazard ratios for the lowest decile of fructosamine were estimated by Cox regression for all-cause (n = 41,388 deaths) and cause-specific mortality during 25 years of follow-up. We observed gradually increased mortality with lower fructosamine in a large segment of the population. In the lowest decile of fructosamine the sex, age, social class and calendar adjusted hazard ratio was 1.20 (95% CI; 1.18-1.27) compared to deciles 2-9. This increased mortality was attenuated after adjustment for six other biomarkers (HR = 1.11 (95% CI; 1.07-1.15)). Haptoglobin, an indicator of chronic inflammation, made the greatest difference in the point estimate. In sensitivity analyses we found an association between low fructosamine and smoking and adjustment for smoking further attenuated the association between low fructosamine and mortality. Low levels of fructosamine in individuals without diabetes were found to be associated with increased mortality. Smoking and chronic inflammation seem to at least partially explain this association but an independent contribution by low fructosamine cannot be excluded.


Biomarker discovery in heterogeneous tissue samples -taking the in-silico deconfounding approach.
For heterogeneous tissues, such as blood, measurements of gene expression are confounded by relative proportions of cell types involved. Conclusions have to rely on estimation of gene expression signals for homogeneous cell populations, e.g. by applying micro-dissection, fluorescence activated cell sorting, or in-silico deconfounding. We studied feasibility and validity of a non-negative matrix decomposition algorithm using experimental gene expression data for blood and sorted cells from the same donor samples. Our objective was to optimize the algorithm regarding detection of differentially expressed genes and to enable its use for classification in the difficult scenario of reversely regulated genes. This would be of importance for the identification of candidate biomarkers in heterogeneous tissues. Experimental data and simulation studies involving noise parameters estimated from these data revealed that for valid detection of differential gene expression, quantile normalization and use of non-log data are optimal. We demonstrate the feasibility of predicting proportions of constituting cell types from gene expression data of single samples, as a prerequisite for a deconfounding-based classification approach.Classification cross-validation errors with and without using deconfounding results are reported as well as sample-size dependencies. Implementation of the algorithm, simulation and analysis scripts are available. The deconfounding algorithm without decorrelation using quantile normalization on non-log data is proposed for biomarkers that are difficult to detect, and for cases where confounding by varying proportions of cell types is the suspected reason. In this case, a deconfounding ranking approach can be used as a powerful alternative to, or complement of, other statistical learning approaches to define candidate biomarkers for molecular diagnosis and prediction in biomedicine, in realistically noisy conditions and with moderate sample sizes.


Metallo-supramolecular self-assembly: the case of triangle-square equilibria.
For the efficient self-assembly of metallo-supramolecular complexes, not only reversibility is required but also two other properties have to be controlled as well: (i) The right binding sites need to be programmed into the building blocks at the appropriate positions. (ii) The building blocks must be rigid enough to support the geometrical arrangement and to avoid the unfavorable entropy effects connected with the conformational fixation of flexible molecules. A series of different bis-pyridyl ligands is reported which self-assemble with (dppp)M(OTf) 2 complexes (dppp = 1,3-bis-(diphenylphosphino)propane; M = Pd (II), Pt (II)) to yield squares and/or triangles as the products. Enthalpic contributions (higher strain in the triangle) and entropic contributions (higher number of triangles from the same building blocks) determine the equilibrium. The effects of concentration, temperature, and solvent properties on the equilibrium have been studied. To characterize the complexes under study, a combination of (1)H, (31)P, and diffusion-ordered NMR spectroscopy, electrospray-ionization Fourier-transform ion-cyclotron-resonance mass spectrometry, and X-ray crystallography is needed. Variable-temperature NMR spectroscopy provides evidence for fast ligand-exchange processes occurring for the Pd complexes, while the Pt complexes exchange ligands much more slowly.


An overview of mortality risk prediction in sepsis.
To review the evolution and development of mortality risk prediction methods as they have been applied to the management of septic patients. Selected relevant articles from the pertinent literature. Theoretical and clinical data on the mortality risk identification, severity of illness scoring systems, and cytokine levels as they relate to mortality in patients with sepsis. All concepts relating to mortality risk prediction, cytokines, severity of illness, and intensive care unit (ICU) mortality were explored and interrelated accordingly. In order to improve the precision of the evaluation of new therapies for the treatment of sepsis, to monitor their utilization and to refine their indications, it has been recommended that mortality risk stratification or severity of illness scoring systems be utilized in clinical trials and in practice. With the increasing influence of managed care on healthcare delivery, there will be an increased demand for techniques to stratify patients for cost-effective allocation of care. Severity of illness scoring systems are widely utilized for patient stratification in the management of cancer and heart disease. However, the use of such systems in patients with sepsis has been limited to application in clinical trial design for assurance of balance among treatment groups. Mortality risk prediction in sepsis has evolved from identification of risk factors, and simple counts of failing organs, to sophisticated techniques that mathematically transform a raw score, comprised of physiologic and/or clinical data, into a predicted risk of death. Most of the developed systems are based on global ICU populations rather than upon sepsis patient databases. A few, newer systems are derived from such databases. However, the overall discriminating ability of the various methods is similar. Mortality prediction has also been carried out from assessments of endotoxin or cytokine (interleukin-1, interleukin-6, tumor necrosis factor) plasma concentrations. While increased levels of these substances have been correlated with increased mortality, difficulties with bioassay and their sporadic appearance in the bloodstream prevent these measurements from being practically applied. The calibration of risk prediction methods comparing predicted with actual mortality across the breadth of risk for a population of patients is excellent, but overall accuracy in individual patient predictions is such that clinical judgment must remain a major part of decision-making. However, as databases of appropriate patient information increase in size and complexity, it may be possible in the future to devise a scoring system that can be relied on to assist in clinical decision-making. Severity of illness scoring systems are widely used in critically ill patients. However, their use in patients with sepsis has largely been limited to a means of stratification in clinical trials. As newer sepsis therapies become available, it may be possible to use such systems for refining their indications, and monitoring their utilization. Finally, as the databases supporting the systems increase in size and complexity, it may be possible to utilize them in clinical decision-making.


Multistability at arbitrary low optical intensities in a metal-dielectric layered structure.
We show that a nonlinear metal-dielectric layered slab of subwavelength thickness and very small average dielectric permittivity displays optical multistable behavior at arbitrary low optical intensities. This is due to the fact that, in the presence of the small linear permittivity, one of the multiple electromagnetic slab states exists no matter how small is the transmitted optical intensity. We prove that multiple states at ultra-low optical intensities can be reached only by simultaneously operating on the incident optical intensity and incidence angle. By performing full wave simulations, we prove that the predicted phenomenology is feasible and very robust.


Fast algorithms for large-scale genome alignment and comparison.
We describe a suffix-tree algorithm that can align the entire genome sequences of eukaryotic and prokaryotic organisms with minimal use of computer time and memory. The new system, MUMmer 2, runs three times faster while using one-third as much memory as the original MUMmer system. It has been used successfully to align the entire human and mouse genomes to each other, and to align numerous smaller eukaryotic and prokaryotic genomes. A new module permits the alignment of multiple DNA sequence fragments, which has proven valuable in the comparison of incomplete genome sequences. We also describe a method to align more distantly related genomes by detecting protein sequence homology. This extension to MUMmer aligns two genomes after translating the sequence in all six reading frames, extracts all matching protein sequences and then clusters together matches. This method has been applied to both incomplete and complete genome sequences in order to detect regions of conserved synteny, in which multiple proteins from one organism are found in the same order and orientation in another. The system code is being made freely available by the authors.


Key Survival Factor, Mcl-1, Correlates with Sensitivity to Combined Bcl-2/Bcl-xL Blockade.
An estimated 40,000 deaths will be attributed to breast cancer in 2016, underscoring the need for improved therapies. Evading cell death is a major hallmark of cancer, driving tumor progression and therapeutic resistance. To evade apoptosis, cancers use antiapoptotic Bcl-2 proteins to bind to and neutralize apoptotic activators, such as Bim. Investigation of antiapoptotic Bcl-2 family members in clinical breast cancer datasets revealed greater expression and more frequent gene amplification of MCL1 as compared with BCL2 or BCL2L1 (Bcl-xL) across three major molecular breast cancer subtypes, Luminal (A and B), HER2-enriched, and Basal-like. While Mcl-1 protein expression was elevated in estrogen receptor α (ERα)-positive and ERα-negative tumors as compared with normal breast, Mcl-1 staining was higher in ERα+ tumors. Targeted Mcl-1 blockade using RNAi increased caspase-mediated cell death in ERα+ breast cancer cells, resulting in sustained growth inhibition. In contrast, combined blockade of Bcl-2 and Bcl-xL only transiently induced apoptosis, as cells rapidly acclimated through Mcl-1 upregulation and enhanced Mcl-1 activity, as measured in situ using Mcl-1/Bim proximity ligation assays. Importantly, MCL1 gene expression levels correlated inversely with sensitivity to pharmacologic Bcl-2/Bcl-xL inhibition in luminal breast cancer cells, whereas no relationship was seen between the gene expression of BCL2 or BCL2L1 and sensitivity to Bcl-2/Bcl-xL inhibition. These results demonstrate that breast cancers rapidly deploy Mcl-1 to promote cell survival, particularly when challenged with blockade of other Bcl-2 family members, warranting the continued development of Mcl-1-selective inhibitors for targeted tumor cell killing.Implications: Mcl-1 levels predict breast cancer response to inhibitors targeting other Bcl-2 family members, and demonstrate the key role played by Mcl-1 in resistance to this drug class. Mol Cancer Res; 15(3); 259-68. ©2016 AACR.


Cytochrome P450 2B enzyme induction defect after 2,2',4,4',5,5'-hexachlorobiphenyl treatment in the fa/fa Zucker rat.
The present study describes the effects of 2,2',4,4',5,5'-hexachlorobiphenyl, a "phenobarbital-like" inducer of hepatic cytochrome P450, on the CYP2B1 and CYP2B2 enzymes in the phenotypically obese fa/fa Zucker rat. The fa/fa Zucker rat demonstrated a markedly lower level of CYP2B1/2B2 enzyme induction, as indicated by reduced enzyme activity (testosterone 16 beta-hydroxylation and pentoxyresorufin O-dealkylation), protein concentration (Western blot), and mRNA (slot blot) than the lean Fa/? rodents after in vivo treatment with 2,2',4,4',5,5'-hexachlorobiphenyl. A primary hepatocyte cell culture system was used to control for possible differences in the disposition of 2,2',4,4',5,5'-hexachlorobiphenyl and hormonal dissimilarity between obese and lean Zucker rats. In agreement with the in vivo study, hepatocytes from fa/fa Zucker rats treated with 2,2',4,4',5,5'-hexachlorobiphenyl exhibited a poor induction response based on measurement of CYP2B1/2B2 mRNA. These data are similar to those reported earlier that demonstrate resistance of the CYP2B1/2B2 genes to the inductive effects of phenobarbital in fa/fa Zucker rats. Apparently a genetic defect in obese Zucker rats impairs the increase in CYP2B1/2B2 gene transcription after treatment with phenobarbital as well as 2,2',4,4',5,5'-hexachlorobiphenyl. This study provides evidence that phenobarbital and "phenobarbital-like" inducers share a common cellular element(s) in the induction process of the CYP2B1/2B2 enzymes.


Multisensory interactions follow the hands across the midline: evidence from a non-spatial visual-tactile congruency task.
Crossing the hands over, whether across the body midline or with respect to each other, leads to measurable changes in spatial compatibility, spatial attention, and frequently to a general decrement in discrimination performance for tactile stimuli. The majority of multisensory crossed hands effects, however, have been demonstrated with explicit or implicit spatial discrimination tasks, raising the question of whether non-spatial discrimination tasks also show spatial effects when the hands are crossed. We designed a novel, non-spatial tactile discrimination task to address this issue. Participants made speeded discriminations of single- versus double-pulse vibrotactile targets, while trying to ignore simultaneous visual distractor stimuli, in both hands uncrossed and hands crossed postures. Tactile discrimination performance was significantly affected by the visual distractors (demonstrating a significant crossmodal congruency effect) and was affected most by visual distractors in the same external location as the tactile target (i.e., spatial modulation), regardless of the posture (uncrossed or crossed) of the hands (i.e., spatial 'remapping' of visual-tactile interactions). Finally, crossing the hands led to a general performance decrement with visual distractors, but not in a control task with unimodal visual or tactile judgements. These results demonstrate, for the first time, significant spatial and postural modulations of crossmodal congruency effects in a non-spatial discrimination task.


Role of indacaterol, a once-daily bronchodilator, in chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow obstruction that can lead to lung destruction and dyspnea. Although there has been a slight reduction in mortality in recent decades, COPD is still a serious health problem that has enormous costs and utilizes significant medical resources. There have been a number of pharmacologic interventions that have been developed for the treatment of COPD. Current guidelines recommend the use of long-acting bronchodilators for the treatment of moderate and severe stage COPD, since they have been shown to improve lung function, respiratory symptoms, and quality of life. Indacaterol is a once-daily beta2-agonist (β2-agonist) delivered by a single-dose dry powder inhaler used for the treatment of COPD. It is currently approved at a dose of 75 μg in the United States and a dose of 150 μg with a maximal dose of 300 μg in Europe and other countries. Several studies show that indacaterol was statistically superior to both long-acting β2-agonist, formoterol and salmeterol, as well as, noninferior to tiotropium. Indacaterol is generally well tolerated and has a good safety profile. Other studies show that there is an additive bronchodilator response with the addition of indacaterol to tiotropium, which would provide a once-daily treatment option for patient with moderate to severe COPD. This review discusses the pharmacokinetic, comparative efficacy and safety data for indacaterol.


Insights into metalloenzyme microenvironments: biomimetic metal complexes with a functional second coordination sphere.
Non-covalent interactions in the second coordination sphere of metalloenzymes play a significant role in determining activity and selectivity. The importance of these interactions is reflected in the increasing number of reports on model complexes with a functional second coordination sphere. These hybrid mimics were developed according to the strategies of modification with functional groups, combination with supramolecular hosts and coupling with polymers, to shed light on the role of non-covalent interactions in metalloenzyme catalysis. This review provides an overview of recent progress in this area. An introduction to native metalloenzymes with an emphasis on the second coordination sphere is also given.


Bioinspired Electrocatalyst for Electrochemical Reduction of N2 to NH3 in Ambient Conditions.
Industrial ammonia production depends heavily on the traditional Haber-Bosch method at the expense of CO2 emissions and large energy consumptions. Artificial fixation of nitrogen to ammonia is therefore regarded as a promising path to yield ammonia in energy-saving conditions. However, a competent electrocatalyst is highly desired, owing to the extremely stable bond of N≡N. In this work, we report Fe2(MoO4)3 nanoparticles as a non-noble-metal electrocatalyst, inspired by nitrogenase enzymes for electrochemically converting nitrogen into ammonia, which achieves a Faradic efficiency of 9.1% and an excellent NH3 yield of 18.16 μg h-1 mg-1 cat in 0.1 M sodium sulfate at -0.6 V vs reversible hydrogen electrode. Also, it has a better ammonia yield rate of 20.09 μg h-1 mg-1 cat in 0.1 M hydrochloric acid. Moreover, this noble-metal-free catalyst exhibits a unique reaction process selectivity and stability compared with the other catalysts working in harsh conditions. The specific reaction processes are analyzed by density functional theoretical calculations to gain insights into the nitrogen reduction reaction (NRR) by this catalyst.


Radium-223 and concomitant therapies in patients with metastatic castration-resistant prostate cancer: an international, early access, open-label, single-arm phase 3b trial.
In the previously reported ALSYMPCA trial in patients with castration-resistant prostate cancer and symptomatic bone metastases, overall survival was significantly longer in patients treated with radium-223 dichloride (radium-223) than in patients treated with placebo. In this study, we investigated safety and overall survival in radium-223 treated patients in an early access programme done after the ALSYMPCA study and before regulatory approval of radium-223. We did an international, prospective, interventional, open-label, single-arm, phase 3b study. Enrolled patients were aged 18 years or older with histologically or cytologically confirmed progressive bone-predominant metastatic castration-resistant prostate cancer with two or more skeletal metastases on imaging (with no restriction as to whether they were symptomatic or asymptomatic; without visceral disease but lymph node metastases were allowed). Patients received intravenous injections of radium-223, 50 kBq/kg (current recommendation 55 kBq/kg after implementation of National Institute of Standards and Technology update on April 18, 2016) every 4 weeks for up to six injections. Other concomitant anticancer therapies were allowed. Primary endpoints were safety and overall survival. The safety and efficacy analyses were done on all patients who received at least one dose of the study drug. The study has been completed, and we report the final analysis here. This study is registered with ClinicalTrials.gov, number NCT01618370, and the European Union Clinical Trials Register, EudraCT number 2012-000075-16. Between July 22, 2012, and Dec 19, 2013, 839 patients were enrolled from 113 sites in 14 countries. 696 patients received one or more doses of radium-223; 403 (58%) of these patients had all six planned injections. Any-grade treatment-emergent adverse events occurred in 523 (75%) of 696 patients; any-grade treatment-emergent adverse events deemed to be related to treatment were reported in 281 (40%) patients. The most common grade 3 or worse treatment-related treatment-emergent adverse events were anaemia in 32 (5%) patients, thrombocytopenia in 15 (2%) patients, neutropenia in ten (1%) patients, and leucopenia in nine (1%) patients. Any grade of serious adverse events were reported in 243 (35%) patients. Median follow-up was 7·5 months (IQR 5-11) and 210 deaths were reported; median overall survival was 16 months (95% CI 13-not available [NA]). In an exploratory analysis of overall survival with predefined factors, median overall survival was longer for: patients with baseline alkaline phosphatase concentration less than the upper limit of normal (ULN; median NA, 95% CI 16 months-NA) than for patients with an alkaline phosphatase concentration equal to or greater than the ULN (median 12 months, 11-15); patients with baseline haemoglobin levels 10 g/dL or greater (median 17 months, 14-NA) than for patients with haemoglobin levels less than 10 g/dL (median 10 months, 8-14); patients with a baseline Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 (median NA, 17 months-NA) than for patients with an ECOG PS of 1 (median 13 months, 11-NA) or an ECOG PS of 2 or more (median 7 months, 5-11); and for patients with no reported baseline pain (median NA, 16 months-NA) than for those with mild pain (median 14 months, 13-NA) or moderate-severe pain (median 11 months, 9-13). Median overall survival was also longer in patients who received radium-223 plus abiraterone, enzalutamide, or both (median NA, 95% CI 16 months-NA) than in those who did not receive these agents (median 13 months, 12-16), and in patients who received radium-223 plus denosumab (median NA, 15 months-NA) than in patients who received radium-223 without denosumab (median 13 months, 12-NA). Our findings show that radium-223 can be safely combined with abiraterone or enzalutamide, which are now both part of the standard of care for patients with metastatic castration-resistant prostate cancer. Furthermore, our findings extend to patients who were asymptomatic at baseline, unlike those enrolled in the pivotal ALSYMPCA study. The findings of prolonged survival in patients treated with concomitant abiraterone, enzalutamide, or denosumab require confirmation in prospective randomised trials. Pharmaceutical Division of Bayer.


Insights From Antiviral Therapy Into Immune Responses to Hepatitis B and C Virus Infection.
There are 257 million persons worldwide with chronic hepatitis B virus (HBV) infection, a leading causes of liver cancer. Almost all adults with acute HBV infection have a rapid immune response to the virus, resulting in life-long immunity, but there is no cure for individuals with chronic HBV infection, which they acquire during early life. The mechanisms that drive the progression of HBV through distinct clinical phases to end-stage liver disease are poorly understood. Likewise, it is not clear whether and how immune responses can be modulated to allow control and/or clearance of intrahepatic HBV DNA. We review the innate and adaptive immune responses to acute and chronic HBV infections and responses to antiviral therapy. Comparisons with hepatitis C virus infection provide insights into the reversibility of innate inflammatory responses and the potential for successful therapy to recover virus-specific memory immune responses.


IMPACT OF A SIMULATED LAPAROSCOPIC TRAINING PROGRAM IN A THREE-YEAR GENERAL SURGERY RESIDENCY.
A General Surgery Residency may last between 2-6 years, depending on the country. A shorter General Surgery Residency must optimize residents' surgical exposure. Simulated surgical training is known to shorten the learning curves, but information related to how it affects a General Surgery Residency regarding clinical exposure is scarce. To analyze the effect of introducing a validated laparoscopic simulated training program in abdominal procedures performed by residents in a three-year General Surgery Residency program. A non-concurrent cohort study was designed. Four-generations (2012-2015) of graduated surgeons were included. Only abdominal procedures in which the graduated surgeons were the primary surgeon were described and analyzed. The control group was of graduated surgeons from 2012 without the laparoscopic simulated training program. Surgical procedures per program year, surgical technique, emergency/elective intervention and hospital-site (main/community hospitals) were described. Interventions of 28 graduated surgeons were analyzed (control group=5; laparoscopic simulated training program=23). Graduated surgeons performed a mean of 372 abdominal procedures, with a higher mean number of medium-to-complex procedures in laparoscopic simulated training program group (48 vs. 30, p=0.02). Graduated surgeons trained with laparoscopic simulated training program performed a higher number of total abdominal procedures (384 vs. 319, p=0.04) and laparoscopic procedures (183 vs. 148, p<0.05). The introduction of laparoscopic simulated training program may increase the number and complexity of total and laparoscopic procedures in a three-year General Surgery Residency.


Prevalence of human papillomavirus in 5,072 consecutive cervical SurePath samples evaluated with the Roche cobas HPV real-time PCR assay.
New commercially available Human Papillomavirus (HPV) assays need to be evaluated in a variety of cervical screening settings. Cobas HPV Test (cobas) is a real-time PCR-based assay allowing for separate detection of HPV genotypes 16 and 18 and a bulk of 12 other high-risk genotypes. The aim of the present study, Horizon, was to assess the prevalence of high-risk HPV infections in an area with a high background risk of cervical cancer, where women aged 23-65 years are targeted for cervical screening. We collected 6,258 consecutive cervical samples from the largest cervical screening laboratory in Denmark serving the whole of Copenhagen. All samples were stored in SurePath media. In total, 5,072 samples were tested with cobas, Hybrid Capture 2 High Risk HPV DNA test (HC2) and liquid-based cytology. Of these, 27% tested positive on cobas. This proportion decreased by age, being 43% in women aged 23-29 years and 10% in women aged 60-65 years. HC2 assay was positive in 20% of samples, and cytology was abnormal (≥ atypical squamous cells of undetermined significance) for 7% samples. When only samples without recent abnormalities were taken into account, 24% tested positive on cobas, 19% on HC2, and 5% had abnormal cytology. The proportion of positive cobas samples was higher than in the ATHENA trial. The age-standardized cobas positivity vs. cytology abnormality was 3.9 in our study and 1.7 in ATHENA. If in Copenhagen the presently used cytology would be replaced by cobas in women above age 30 years, an extra 11% of women would based on historical data be expected to have a positive cobas test without an underlying cervical intraepithelial lesion grade 3 or worse. Countries with a high prevalence of HPV infections should therefore proceed to primary HPV-based cervical screening with caution.


A reappraisal of the quantitative relationship between sugar intake and dental caries: the need for new criteria for developing goals for sugar intake.
There is a clear relation between sugars and caries. However, no analysis has yet been made of the lifetime burden of caries induced by sugar to see whether the WHO goal of 10% level is optimum and compatible with low levels of caries. The objective of this study was to re-examine the dose-response and quantitative relationship between sugar intake and the incidence of dental caries and to see whether the WHO goal for sugar intake of 10% of energy intake (E) is optimum for low levels of caries in children and adults. Analyses focused on countries where sugar intakes changed because of wartime restrictions or as part of the nutritional transition. A re-analysis of the dose-response relation between dietary sugar and caries incidence in teeth with different levels of susceptibility to dental caries in nationally representative samples of Japanese children. The impact of fluoride on levels of caries was also assessed. Meticulous Japanese data on caries incidence in two types of teeth show robust log-linear relationships to sugar intakes from 0%E to 10%E sugar with a 10 fold increase in caries if caries is assessed over several years' exposure to sugar rather than only for the first year after tooth eruption. Adults aged 65 years and older living in water fluoridated areas where high proportions of people used fluoridated toothpastes, had nearly half of all tooth surfaces affected by caries. This more extensive burden of disease in adults does not occur if sugar intakes are limited to <3% energy intake. There is a robust log-linear relationship of caries to sugar intakes from 0%E to 10%E sugar. A 10%E sugar intake induces a costly burden of caries. These findings imply that public health goals need to set sugar intakes ideally <3%E with <5%E as a pragmatic goal, even when fluoride is widely used. Adult as well as children's caries burdens should define the new criteria for developing goals for sugar intake.


The Role of Ovarian Suppression in Premenopausal Women With Hormone Receptor-Positive Early-Stage Breast Cancer.
The optimal adjuvant endocrine therapy in premenopausal women with early-stage breast cancer is yet to be elucidated. Studies have demonstrated that women who experience cessation of ovarian function after chemotherapy (chemotherapy-induced amenorrhea) may experience improved survival. These findings, however, have not been replicated when pharmacologic or surgical interventions have been used to stop ovarian function (eg, gonadotropin-releasing hormone agonists, oophorectomy, or ovarian irradiation) in combination with an endocrine agent such as tamoxifen or an aromatase inhibitor. Recent large phase III clinical trials, including the Austrian Breast and Colorectal Cancer Study Group trial (ABCSG-12), Suppression of Ovarian Function Trial (SOFT), and Tamoxifen and Exemestane Trial (TEXT), did not demonstrate an improvement in disease-free survival with ovarian suppression in the overall population. However, subgroup analyses suggest that women at high risk for recurrence, including very young women or those who have received chemotherapy, may benefit from the addition of ovarian suppression. Still, toxicity and adverse effects on patient-reported outcomes were more frequent in patients who received ovarian suppression; these included more menopausal and sexual dysfunction symptoms, diabetes, hypertension, and osteoporosis. This review will summarize the experience with ovarian suppression in the adjuvant setting for the treatment of premenopausal early-stage breast cancer and offer recommendations for clinical management.


New neurons follow the flow of cerebrospinal fluid in the adult brain.
In the adult brain, neuroblasts born in the subventricular zone migrate from the walls of the lateral ventricles to the olfactory bulb. How do these cells orient over such a long distance and through complex territories? Here we show that neuroblast migration parallels cerebrospinal fluid (CSF) flow. Beating of ependymal cilia is required for normal CSF flow, concentration gradient formation of CSF guidance molecules, and directional migration of neuroblasts. Results suggest that polarized epithelial cells contribute important vectorial information for guidance of young, migrating neurons.


National Parks in Savannah Africa: Ecological requirements of parks must be balanced against socioeconomic constraints in their environs.
A national park is as integral to its regional environment as it is to the nation. Whether one wants to manage it that way or not, a park is dependent on the resources-human and physiobiological-of the environs, just as the environs are modified by the park's existence. This view may not jibe with the spirit of those who strive to protect a patch of old-time Africa as a refuge of serenity and stability in a world of tumult and change. But the park has its own ecology, just as does any creature within it, although the park's, being more abstract, is more difficult to discern. Planned or not, a park's future is even more enmeshed with the region's future than with the nation's. The ramifications of this relationship, especially the socioeconomic ones, are not always recognized, with the result that the enmeshing process sometimes sounds like a crunching of the gears. The worlds on both sides of the park boundary would get along better if there were a clear indication of what each can do for the other. By contrast, if they spend their energy resisting one another, there is little doubt as to which must be the ultimate "winner."


Cerebellar Intermittent Theta-Burst Stimulation and Motor Control Training in Individuals with Cervical Dystonia.
There is emerging evidence that cervical dystonia is a neural network disorder with the cerebellum as a key node. The cerebellum may provide a target for neuromodulation as a therapeutic intervention in cervical dystonia. This study aimed to assess effects of intermittent theta-burst stimulation of the cerebellum on dystonia symptoms, quality of life, hand motor dexterity and cortical neurophysiology using transcranial magnetic stimulation. Sixteen participants with cervical dystonia were randomised into real or sham stimulation groups. Cerebellar neuromodulation was combined with motor training for the neck and an implicit learning task. The intervention was delivered over 10 working days. Outcome measures included dystonia severity and pain, quality of life, hand dexterity, and motor-evoked potentials and cortical silent periods recorded from upper trapezius muscles. Assessments were taken at baseline and after 5 and 10 days, with quality of life also measured 4 and 12 weeks later. Intermittent theta-burst stimulation improved dystonia severity (Day 5, -5.44 points; p = 0.012; Day 10, -4.6 points; p = 0.025), however, effect sizes were small. Quality of life also improved (Day 5, -10.6 points, p = 0.012; Day 10, -8.6 points, p = 0.036; Week 4, -12.5 points, p = 0.036; Week 12, -12.4 points, p = 0.025), with medium or large effect sizes. There was a reduction in time to complete the pegboard task pre to post intervention (both p < 0.008). Cortical neurophysiology was unchanged by cerebellar neuromodulation. Intermittent theta-burst stimulation of the cerebellum may improve cervical dystonia symptoms, upper limb motor control and quality of life. The mechanism likely involves promoting neuroplasticity in the cerebellum although the neurophysiology remains to be elucidated. Cerebellar neuromodulation may have potential as a novel treatment intervention for cervical dystonia, although larger confirmatory studies are required.


Genome sequence of a Lancefield group C Streptococcus zooepidemicus strain causing epidemic nephritis: new information about an old disease.
Outbreaks of disease attributable to human error or natural causes can provide unique opportunities to gain new information about host-pathogen interactions and new leads for pathogenesis research. Poststreptococcal glomerulonephritis (PSGN), a sequela of infection with pathogenic streptococci, is a common cause of preventable kidney disease worldwide. Although PSGN usually occurs after infection with group A streptococci, organisms of Lancefield group C and G also can be responsible. Despite decades of study, the molecular pathogenesis of PSGN is poorly understood. As a first step toward gaining new information about PSGN pathogenesis, we sequenced the genome of Streptococcus equi subsp. zooepidemicus strain MGCS10565, a group C organism that caused a very large and unusually severe epidemic of nephritis in Brazil. The genome is a circular chromosome of 2,024,171 bp. The genome shares extensive gene content, including many virulence factors, with genetically related group A streptococci, but unexpectedly lacks prophages. The genome contains many apparently foreign genes interspersed around the chromosome, consistent with the presence of a full array of genes required for natural competence. An inordinately large family of genes encodes secreted extracellular collagen-like proteins with multiple integrin-binding motifs. The absence of a gene related to speB rules out the long-held belief that streptococcal pyrogenic exotoxin B or antibodies reacting with it singularly cause PSGN. Many proteins previously implicated in GAS PSGN, such as streptokinase, are either highly divergent in strain MGCS10565 or are not more closely related between these species than to orthologs present in other streptococci that do not commonly cause PSGN. Our analysis provides a comparative genomics framework for renewed appraisal of molecular events underlying APSGN pathogenesis.


The origin of bounded rationality and intelligence.
Rational economic behavior in which individuals maximize their own self-interest is only one of many possible types of behavior that arise from natural selection. Given an initial population of individuals, each assigned a purely arbitrary behavior with respect to a binary choice problem, and assuming that offspring behave identically to their parents, only those behaviors linked to reproductive success will survive, and less successful behaviors will disappear exponentially fast. This framework yields a single evolutionary explanation for the origin of several behaviors that have been observed in organisms ranging from bacteria to humans, including risk-sensitive foraging, risk aversion, loss aversion, probability matching, randomization, and diversification. The key to understanding which types of behavior are more likely to survive is how behavior affects reproductive success in a given population's environment. From this perspective, intelligence is naturally defined as behavior that increases the likelihood of reproductive success, and bounds on rationality are determined by physiological and environmental constraints.


Expression and radiolabeling of recombinant proteins containing a phosphorylation motif.
Radiolabeled proteins are useful in basic and clinical research. Current methods available for radiolabeling proteins involve chemical derivatization, resulting in multiple additions of radionuclides at random sites. A method designed to specifically localize the radionuclide to a unique site will offer advantages of control and predictability in radiolabeling. We have studied the usefulness of a prokaryotic expression vector by incorporating the coding sequence of a consensus phosphorylation motif (Kemptide) for the cAMP-dependent protein kinase A immediately upstream to the multiple cloning site. This vector was used to express five different recombinant proteins with a phosphorylation site at the amino terminus. In addition, the phosphorylation motif was introduced into two other proteins and expressed in yeast. The genetically engineered proteins were purified to homogeneity by affinity chromatography and radiolabeled with [gamma32P]ATP in vitro. All seven proteins used in this study could be expressed with the phosphorylation sequence at their amino terminus and specifically labeled without loss of biological activity. This strategy allows the option of labeling proteins to high or low specific radioactivity and holds potential for in vitro binding and in vivo localization studies.


The influence of sudden perturbations on trunk muscle activity and intra-abdominal pressure while standing.
Unexpected ventral and dorsal perturbations and expected, self-induced ventral perturbations were delivered to the trunk by suddenly loading a vest strapped to the torso. Six male subjects were measured for intra-abdominal pressure (IAP) and intra-muscular electromyography of the transversus abdominis (TrA), obliquus internus abdominis (OI), obliquus externus abdominis (OE) and rectus abdominis (RA) muscles. Erector spinae (ES) activity was recorded using surface electromyography. Displacements of the trunk and head were registered using a video-based system. Unexpected ventral loading produced activity in TrA, OI, OE and RA, and an IAP increase well in advance of activity from ES. Expected ventral loading produced pre-activation of all muscles and an increased IAP prior to the perturbation. The TrA was always the first muscle active in both the unexpected and self-loading conditions. Of the two ventral loading conditions, forward displacement of the trunk was significantly reduced during the self-loading. Unexpected dorsal loading produced coincident activation of TrA, OI, OE, RA and ES. These results indicate a response of the trunk muscles to sudden expected and unexpected ventral loadings other than the anticipated immediate extensor torque production through ES activation. It is suggested that the increase in IAP is a mechanism designed to improve the stability of the trunk through a stiffening of the whole segment.


In Vitro Interaction between Isavuconazole and Tacrolimus, Cyclosporin A, or Sirolimus against Aspergillus Species.
The interaction of isavuconazole with immunosuppressors (tacrolimus, cyclosporin A, or sirolimus) against 30 Aspergillus isolates belonging to the most common species responsible for invasive aspergillosis in humans (Aspergillus flavus, Aspergillus fumigatus, Aspergillus nidulans, Aspergillus niger, and Aspergillus terreus) was evaluated in vitro by a microdilution checkerboard technique based on the EUCAST reference method for antifungal susceptibility testing. The interpretation of the results was performed based on the fractional inhibitory concentration index. The combination of isavuconazole with tacrolimus, cyclosporin A, or sirolimus, was synergistic for 56, 20, or 10% of the isolates, respectively. Interestingly synergy of the combination of isavuconazole with tacrolimus was also achieved for the majority of azole-resistant isolates of A. fumigatus, and for all A. niger isolates with isavuconazole minimal inhibitory concentrations ≥ 8 µg/mL. Antagonistic interactions were never observed for any combination tested.


Dissociation of rugose-dependent short-term memory component from memory consolidation in Drosophila.
Extensive investigations show several molecular and neuroanatomical mechanisms underlying short-lived and long-lasting memory in Drosophila. At the molecular level, the genetic pathway of memory formation, which was obtained through mutant research, seems to occur sequentially. So far, studies of Drosophila mutants appear to support the idea that mutants defective in short-term memory (STM) are always associated with long-term memory (LTM) impairment. At the neuroanatomical level, distinct memory traces are partially independently distributed. However, whether memory phase dissociation also exists at the molecular level remains unclear. Here, we report on molecular separation of STM and consolidated memory through genetic dissection of rugose mutants. Mutants in the rugose gene, which encodes an evolutionarily conserved A-kinase anchor protein, show immediate memory defects as assayed through aversive olfactory conditioning. Intriguingly, two well-defined consolidated memory components, anesthesia-resistant memory and protein synthesis-dependent LTM, are both normal in spite of the defective immediate memory after 10-session massed and spaced training. Moreover, rugose genetically interacts with cyclic AMP-protein kinase A signaling during STM formation. Considering our previous study that AKAP Yu specifically participates in LTM formation, these results suggest that there exists a molecular level of memory phase dissociation with distinct AKAPs in Drosophila.


Effect of cyclic redox oscillations on water quality in freshwater acid sulfate soil wetlands.
Restoration of acid sulfate soil (ASS) wetlands by freshwater re-flooding can lead to the reformation of various Fe(II) and reduced inorganic sulfur (RIS) species in surface soil layers. However, in many locations, wetland water levels undergo large seasonal fluctuations that drive extreme redox oscillations. Newly formed RIS species [e.g. greigite, mackinawite, nano-pyrite and S(0)] and Fe(II) are vulnerable to rapid oxidation during dry periods and may generate substantial acidity. Rainfall following a dry period may then mobilise acidity and metal cations in surface waters prior to eventual recovery in pH by re-establishment of reducing conditions. We explore this dry-wet transition by subjecting soil samples from two freshwater re-flooded ASS wetlands to oxidative incubation for up to 130days followed by re-flooding simulation for 84days. During very early stages of re-flooding (up to 7days) there was an initial pulse-release of acidity, and trace metals/metalloids (Al, Mn, Zn and As). This was followed by a rapid reversion to anoxia, and Fe(III) and SO4 reducing conditions which generated alkalinity, ameliorated acidity and sequestered Fe, S, Zn, Mn and As. Field-observations of surface water quality in an ASS wetland at a sub-catchment scale also confirms re-establishment of SO4 reducing conditions and recovery of pH within ~4-8weeks of re-flooding after dry periods. These observations suggest that retaining surface water in ASS wetlands for ~8weeks after a dry-wet transition will allow sufficient time for alkalinity producing reductive processes to ameliorate most surface water acidity. Although management of freshwater re-flooded ASS wetlands in a highly dynamic climate will remain challenging over the long term and the post-remediation effectiveness of the method depends on initial soil characteristics, knowledge of the timing of redox oscillations and the associated changes in water geochemistry can be helpful for mitigating the risks to downstream estuarine water quality.


Epigenetic regulation of DNA methyltransferases: DNMT1 and DNMT3B in gliomas.
The role of epigenetics and significance of aberrant gene regulation in etiology of cancer is a well-established phenomenon. The hallmark of cancer epigenetics is aberrant DNA methylation consisting of global hypomethylation and regional hypermethylation of tumor suppressor genes (TSGs) by DNA methyltransferases (DNMTs). In mammals, DNA methylation is catalyzed by DNMTs encoded by DNMT1, DNMT3A, and DNMT3B. Interestingly, little is known about variation in the methylation status of epigenetic regulators themselves in gliomas. Here, we report significant overexpression of DNMT1 and DNMT3B. A study of the methylation status and histone modifications at the promoter region of DNA methyltransferase I (DNMT1) gene revealed an unmethylated DNA promoter, similar to that detected in normal brain tissues. However, a differential histone code with distinct euchromatin marks--AcH3, AcH4, and H3k4me2--was specifically detected in tumors, unlike in normal brain tissues, which were found predominantly enriched with heterochromatin marks such as H3K9me2 and H3K27me3. In contrast, a differential methylation pattern of DNMT3B gene promoter occurred in glioma tumors, wherein it was found hypomethylated. Transcriptional silencing by CpG island methylation is a prevalent mechanism for inactivation of TSGs. Inhibiting DNMTs by 5-azacytidine (DNMT inhibitor) treatment led to significant inhibition of expression of DNMT1 and DNMT3B and enhanced expression of TSGs such as PTEN and p21 analyzed in this study. Our studies have identified effects of increased presence of DNMTs on inhibition of tumor suppressors that are epigenetically silenced in gliomas, thereby leading to aberrant regulation of cell cycle progression and failure to maintain genomic stability.


Molecularly imprinted polymer surfaces as solid-phase extraction sorbents for the extraction of 2-nitrophenol and isomers from environmental water.
The novel surface molecularly imprinted polymer (MIP) with 2-nitrophenol (2-NP) as the template has been prepared and used as the adsorbent for the solid-phase extraction (SPE). The selectivity of the polymer was checked toward several selected nitrophenols (NPs) such as 2-NP, 3-nitrophenol (3-NP), 4-nitrophenol (4-NP) and 2,4,6-trichlorophenol (2,4,6-TCP). Under the optimized conditions, high sensitivity (detection limits: 0.07-0.12 ng/mL) and good reproducibility of analytes (2.3-4.8% for four cycles) were achieved. Then, the method was applied for the analysis of selected phenols in spiked tap, lake and river water samples. High recoveries (>83.3%) for nitrophenols (NPs) were obtained, but lower recoveries (<63.4%) were achieved for 2,4,6-TCP. The method was found to be linear in the range of 1-300 ng/mL with correlation coefficients (R(2) ) greater than 0.99 and repeatability relative standard deviation (RSD) below 7.2% in all cases. For analysis of 120 mL water samples, the method detection limits (LODs) ranged from 0.10 to 0.22 ng/mL and the limit of quantification (LOQs) from 0.33 to 0.72 ng/mL. These results showed the suitability of the MIP-SPE method for the selective extraction of a group of structurally related isomeric compounds.


Using titanium complexes to defeat cancer: the view from the shoulders of titans.
When the first titanium complex with anticancer activity was identified in the 1970s, it was attractive, based on the presence of the dichloride unit in TiCl2Cp2 (Cp = η-C5H5)2, to assume its mode of biological action was closely aligned with cisplatin [cis-PtCl2(NH3)2]. Over the intervening 40 years however a far more complicated picture has arisen indicating multiple cellular mechanisms of cellular action can be triggered by titanium anti-cancer agents. This tutorial review aims to unpick the historical data and provide new researchers, without an explicit cancer biology background, a contemporary interpretation of both older and newer literature and to review the best techniques for attaining the identities of the biologically active titanium species and how these interact with the cancer cellular machinery.


Phytochemical profiling and evaluation of modified resazurin microtiter plate assay of the roots of Trillium govanianum.
Trillium govanianum Wall. ex D. Don (Melanthiaceae alt. Trilliaceae), is native to the Himalayas. The present study, for the first time, was undertaken to explore the antimicrobial potential, to determine the minimum inhibitory concentration (MIC) values of the methanol extract of the roots of Trillium govanianum and its solid phase extraction (SPE) fractions by using resazurin microtiter assay (REMA) against Gram positive and Gram negative bacterial registered strains and to carry out phytochemical analysis. The remarkable amount of gallic acid equivalent phenolic and quercetin equivalent flavonoid content was manifested by MeOH extract (20.27 ± 3.03 mg GAE/g DW and 9.25 ± 0.50 mg QE/g DW respectively). The GC/MS analysis revealed the presence saturated and unsaturated components. Considerable level of antibacterial potential against Gram-positive bacteria (MIC: 2.5-0.009 mg/mL) than against Gram-negative bacteria (MIC: 2.5-0.165 mg/mL) were observed. The use of microtiter plates has the advantage of lower cost, fast and quantitative results.


ACC/AATS/AHA/ASE/ASNC/SCAI/SCCT/STS 2017 Appropriate Use Criteria for Coronary Revascularization in Patients With Stable Ischemic Heart Disease : A Report of the American College of Cardiology Appropriate Use Criteria Task Force, American Association for Thoracic Surgery, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and Society of Thoracic Surgeons.
The American College of Cardiology, Society for Cardiovascular Angiography and Interventions, Society of Thoracic Surgeons, and American Association for Thoracic Surgery, along with key specialty and subspecialty societies, have completed a 2-part revision of the appropriate use criteria (AUC) for coronary revascularization. In prior coronary revascularization AUC documents, indications for revascularization in acute coronary syndromes and stable ischemic heart disease (SIHD) were combined into 1 document. To address the expanding clinical indications for coronary revascularization, and to align the subject matter with the most current American College of Cardiology/American Heart Association guidelines, the new AUC for coronary artery revascularization were separated into 2 documents addressing SIHD and acute coronary syndromes individually. This document presents the AUC for SIHD.Clinical scenarios were developed to mimic patient presentations encountered in everyday practice. These scenarios included information on symptom status; risk level as assessed by noninvasive testing; coronary disease burden; and, in some scenarios, fractional flow reserve testing, presence or absence of diabetes, and SYNTAX score. This update provides a reassessment of clinical scenarios that the writing group felt were affected by significant changes in the medical literature or gaps from prior criteria. The methodology used in this update is similar to the initial document but employs the recent modifications in the methods for developing AUC, most notably, alterations in the nomenclature for appropriate use categorization.A separate, independent rating panel scored the clinical scenarios on a scale of 1 to 9. Scores of 7 to 9 indicate that revascularization is considered appropriate for the clinical scenario presented. Scores of 1 to 3 indicate that revascularization is considered rarely appropriate for the clinical scenario, whereas scores in the mid-range of 4 to 6 indicate that coronary revascularization may be appropriate for the clinical scenario.As seen with the prior coronary revascularization AUC, revascularization in clinical scenarios with high symptom burden, high-risk features, and high coronary disease burden, as well as in patients receiving antianginal therapy, are deemed appropriate. Additionally, scenarios assessing the appropriateness of revascularization before kidney transplantation or transcatheter valve therapy are now rated. The primary objective of the AUC is to provide a framework for the assessment of practice patterns that will hopefully improve physician decision making.


Visualization of shape motions in shape space.
Analysis of dynamic object deformations such as cardiac motion is of great importance, especially when there is a necessity to visualize and compare the deformation behavior across subjects. However, there is a lack of effective techniques for comparative visualization and assessment of a collection of motion data due to its 4-dimensional nature, i.e., timely varying three-dimensional shapes. From the geometric point of view, the motion change can be considered as a function defined on the 2D manifold of the surface. This paper presents a novel classification and visualization method based on a medial surface shape space, in which two novel shape descriptors are defined, for discriminating normal and abnormal human heart deformations as well as localizing the abnormal motion regions. In our medial surface shape space, the geodesic distance connecting two points in the space measures the similarity between their corresponding medial surfaces, which can quantify the similarity and disparity of the 3D heart motions. Furthermore, the novel descriptors can effectively localize the inconsistently deforming myopathic regions on the left ventricle. An easy visualization of heart motion sequences on the projected space allows users to distinguish the deformation differences. Our experimental results on both synthetic and real imaging data show that this method can automatically classify the healthy and myopathic subjects and accurately detect myopathic regions on the left ventricle, which outperforms other conventional cardiac diagnostic methods.


Phosphorylated α-synuclein in Parkinson's disease: correlation depends on disease severity.
α-Synuclein (α-syn) is a key protein in Parkinson's disease (PD), and one of its phosphorylated forms, pS129, is higher in PD patients than healthy controls. However, few studies have examined its levels in longitudinally collected cerebrospinal fluid (CSF) or in preclinical cases. In this study, CSF and clinical data were contributed by >300 subjects from three cohorts (the longitudinal DATATOP cohort, a large cross-sectional cohort, and a cohort of LRRK2 mutation carriers). Consistent with our previous observation that CSF pS129 positively correlated with Unified Parkinson's Disease Rating Scale (UPDRS) scores, CSF pS129 in the DATATOP cohort increased over approximately two years of disease progression (mean change 5.60 pg/ml, p = 0.050). Intriguingly, in the DATATOP cohort, pS129 negatively correlated with UPDRS scores at the baseline (R = -0.244, p = 0.017), but not final point, suggesting that this association may depend on disease stage. Reanalysis of our previous cohort with stratification by PD stage, and addition of a cohort of LRRK2 mutation carriers with very early/preclinical PD, supported the idea that the relationship between CSF pS129 and disease severity over a wider range of PD stages might be represented with a U-shaped curve, in which lower pS129 levels correlated with worse clinical condition at early stages, but better condition at later stages. The observation of a negative-to-positive transition of correlation of pS129 to disease severity as PD progresses could have profound impact on how pS129 is used as a biomarker clinically as well as in modeling PD experimentally.


Understanding linkages between bullying and suicidal ideation in a national sample of LGB and heterosexual youth in the United States.
While there is an extant research base regarding suicidal ideation in relation to bullying and peer harassment, how findings may be similar and different for lesbian, gay, and bisexual (LGB) and non-LGB youth is less well understood. To address this gap, we analyzed data from 5,542 13- to 18-year-old youth who were nationally surveyed online in the United States in 2010. Results suggest that the relative odds of suicidal ideation are elevated for youth who are victims of bullying (OR = 5.61, 95 % CI, 4.11, 7.64), as well as those who are victims of peer harassment (OR = 2.06, 95 % CI, 1.53, 2.79). Within the context of other important factors, bullying was associated with odds of suicidal ideation twice that of non-victimized youth (aOR = 2.02, 95 % CI, 1.30, 3.13). Within sexual identity, the relation between bullying and suicidal ideation was particularly strong for gay, lesbian, and queer youth, even after adjusting for other influential factors (aOR = 6.29, 95 % CI, 2.69, 14.66). Across sexual identities, the odds of suicidal ideation are higher for bisexual youth (aOR = 1.77, 95 % CI, 1.23, 2.55) but not for other sexual minority youth when compared with otherwise similar heterosexual youth. Other factors, including depressive symptomatology and low self-esteem, were also predictive of recent ideation across all sexual identities. Findings highlight the complexity of bullying and suicidal ideation. Furthermore, given the relation between bullying and suicidal ideation, and the disproportionate level of bullying experienced by LGB youth, our findings suggest the need for more protective environments for LGB youth.


Inflammatory myofibroblastic tumor causing ileoileal intussusception: an unusual cause of an unusual neoplasm in an adult, with a clinicopathological review of the literature.
An inflammatory myofibroblastic tumor (IMT) of the ileum is a very rare lesion of the gastrointestinal tract. A 36-year-old female presented with abdominal fullness and colicky pain of 5 days' duration. Plain abdominal radiography showed an intestinal obstruction with dilated jejunal loops. Abdominal computed tomography and ultrasonography demonstrated a well-defined intraluminal solid mass surrounded by the typical mural layers of an invaginated ileum. The patient then underwent an exploratory laparotomy under a clinical diagnosis of intussusception caused by a small bowel tumor. The surgical findings revealed a large mass leading to an ileoileal intussusception, with regional lymph node enlargement and a small bowel resection accompanied by lymph node dissection was performed. The definitive diagnosis of IMT was confirmed by both conventional histopathology and minute immunohistochemistry.


DNA internal motions within nucleosomes during the cell cycle and as a function of ionic strength.
We have used 31P NMR spectra to show that DNA internal motions are greatly hindered within oligonucleosomes. The fluctuations seem to be a function of both the cell cycle and the number of nucleosomes interlinked. Namely, the resonance areas, directly related to unbound phosphate, are consistently smaller in M-phase than in S-phase; at the same time, the resonance line width, inversely related to base plane, deoxyribose, and phosphate internal motions, is consistently larger in mononucleosomes than in oligonucleosomes. In all cases, the removal of chromosomal proteins, by a progressive increase of ionic strength up to 2 M NaCl, increases the internal motion, as monitored by a decrease in line width toward that of free DNA. While for both oligo- and mononucleosomes in S-phase the decrease in line width is strictly correlated to a sharp increase in resonance area, in M-phase it is not, with the 31P resonance area rather low even at 2.0 M NaCl extraction. Similarly, while S-phase 31P line widths steadily grow from mono- to oligonucleosomes, in M-phase they do not. Moreover, the increase of the ionic strength to 0.6 M NaCl, as compared to 0.35, 1.2, and 2 M NaCl, displays significant variations on 31P line width and resonance area, independent of the cell cycle phase and the number of nucleosomes interlinked. These observations agree with earlier suggestions on the differential role of the various chromosomal protein subfractions, known to preferentially dissociate at the different ionic strengths in question, in the sealing of mononucleosomes and in the overall stability of polynucleosomes.


A beta -hairpin structure in a 13-mer peptide that binds alpha -bungarotoxin with high affinity and neutralizes its toxicity.
Snake-venom alpha-bungarotoxin is a member of the alpha-neurotoxin family that binds with very high affinity to the nicotinic acetylcholine receptor (AChR) at the neuromuscular junction. The structure of the complex between alpha-bungarotoxin and a 13-mer peptide (WRYYESSLEPYPD) that binds the toxin with high affinity, thus inhibiting its interactions with AChR with an IC(50) of 2 nM, has been solved by (1)H-NMR spectroscopy. The bound peptide folds into a beta-hairpin structure created by two antiparallel beta-strands, which combine with the already existing triple-stranded beta-sheet of the toxin to form a five-stranded intermolecular, antiparallel beta-sheet. Peptide residues Y3(P), E5(P), and L8(P) have the highest intermolecular contact area, indicating their importance in the binding of alpha-bungarotoxin; W1(P), R2(P), and Y4(P) also contribute significantly to the binding. A large number of characteristic hydrogen bonds and electrostatic and hydrophobic interactions are observed in the complex. The high-affinity peptide exhibits inhibitory potency that is better than any known peptide derived from AChR, and is equal to that of the whole alpha-subunit of AChR. The high degree of sequence similarity between the peptide and various types of AChRs implies that the binding mode found within the complex might possibly mimic the receptor binding to the toxin. The design of the high-affinity peptide was based on our previous findings: (i) the detection of a lead peptide (MRYYESSLKSYPD) that binds alpha-bungarotoxin, using a phage-display peptide library, (ii) the information about the three-dimensional structure of alpha-bungarotoxin/lead-peptide complex, and (iii) the amino acid sequence analysis of different AChRs.


Measuring coherence functions using non-parallel double slits.
We present an experimental method for the fast measurement of both the spectral (spatial) and complex degrees of coherence of an optical field using only a binary amplitude mask and a detector array. We test the method by measuring a two-dimensional spectral degree of coherence function created by a broadband thermal source. The results are compared to those expected by the van Cittert-Zernike theorem and found to agree well in both amplitude and phase.


SPI-23 of S. Derby: role in adherence and invasion of porcine tissues.
Salmonella enterica serovars Derby and Mbandaka are isolated from different groups of livestock species in the UK. S. Derby is predominantly isolated from pigs and turkeys and S. Mbandaka is predominantly isolated from cattle and chickens. Alignment of the genome sequences of two isolates of each serovar led to the discovery of a new putative Salmonella pathogenicity island, SPI-23, in the chromosome sequence of S. Derby isolates. SPI-23 is 37 kb in length and contains 42 ORFs, ten of which are putative type III effector proteins. In this study we use porcine jejunum derived cell line IPEC-J2 and in vitro organ culture of porcine jejunum and colon, to characterise the association and invasion rates of S. Derby and S. Mbandaka, and tissue tropism of S. Derby respectively. We show that S. Derby invades and associates to an IPEC-J2 monolayer in significantly greater numbers than S. Mbandaka, and that S. Derby preferentially attaches to porcine jejunum over colon explants. We also show that nine genes across SPI-23 are up-regulated to a greater degree in the jejunum compared to the colon explants. Furthermore, we constructed a mutant of the highly up-regulated, pilV-like gene, potR, and find that it produces an excess of surface pili compared to the parent strain which form a strong agglutinating phenotype interfering with association and invasion of IPEC-J2 monolayers. We suggest that potR may play a role in tissue tropism.


Association of vascular fluoride uptake with vascular calcification and coronary artery disease.
The feasibility of a fluoride positron emission tomography/computed tomography (PET/CT) scan for imaging atherosclerosis has not been well documented. The purpose of this study was to assess fluoride uptake of vascular calcification in various major arteries, including coronary arteries. We retrospectively reviewed the imaging data and cardiovascular history of 61 patients who received whole-body sodium [¹⁸F]fluoride PET/CT studies at our institution from 2009 to 2010. Fluoride uptake and calcification in major arteries, including coronary arteries, were analyzed by both visual assessment and standardized uptake value measurement. Fluoride uptake in vascular walls was demonstrated in 361 sites of 54 (96%) patients, whereas calcification was observed in 317 sites of 49 (88%) patients. Significant correlation between fluoride uptake and calcification was observed in most of the arterial walls, except in those of the abdominal aorta. Fluoride uptake in coronary arteries was demonstrated in 28 (46%) patients and coronary calcifications were observed in 34 (56%) patients. There was significant correlation between history of cardiovascular events and presence of fluoride uptake in coronary arteries. The coronary fluoride uptake value in patients with cardiovascular events was significantly higher than in patients without cardiovascular events. sodium [¹⁸F]fluoride PET/CT might be useful in the evaluation of the atherosclerotic process in major arteries, including coronary arteries. An increased fluoride uptake in coronary arteries may be associated with an increased cardiovascular risk.


The fragile X syndrome.
An amplification of a highly unstable DNA element has been identified at the fragile X locus in Xq27.3. This sequence appears to be both the source of the primary mutation causing the fragile X syndrome, apparently having its causative effect through the methylation of the FMR-1 HTF island and the region of cytogenetic fragility. The direct analysis of the genotype of carrier and affected individuals can be used as a direct diagnosis tool which will improve both the accuracy and speed of diagnosis. The identification of hereditary unstable DNA in a disease with such a wide level of non-penetrance and variable phenotype may give clues as to the basis of non-penetrance in other human genetic disorders.