A signaling mechanism coupling netrin-1/deleted in colorectal cancer chemoattraction to SNARE-mediated exocytosis in axonal growth cones.
Directed cell migration and axonal guidance are essential steps in neural development. Both processes are controlled by specific guidance cues that activate the signaling cascades that ultimately control cytoskeletal dynamics. Another essential step in migration and axonal guidance is the regulation of plasmalemma turnover and exocytosis in leading edges and growth cones. However, the cross talk mechanisms linking guidance receptors and membrane exocytosis are not understood. Netrin-1 is a chemoattractive cue required for the formation of commissural pathways. Here, we show that the Netrin-1 receptor deleted in colorectal cancer (DCC) forms a protein complex with the t-SNARE (target SNARE) protein Syntaxin-1 (Sytx1). This interaction is Netrin-1 dependent both in vitro and in vivo, and requires specific Sytx1 and DCC domains. Blockade of Sytx1 function by using botulinum toxins abolished Netrin-1-dependent chemoattraction of axons in mouse neuronal cultures. Similar loss-of-function experiments in the chicken spinal cord in vivo using dominant-negative Sytx1 constructs or RNAi led to defects in commissural axon pathfinding reminiscent to those described in Netrin-1 and DCC loss-of-function models. We also show that Netrin-1 elicits exocytosis at growth cones in a Sytx1-dependent manner. Moreover, we demonstrate that the Sytx1/DCC complex associates with the v-SNARE (vesicle SNARE) tetanus neurotoxin-insensitive vesicle-associated membrane protein (TI-VAMP) and that knockdown of TI-VAMP in the commissural pathway in the spinal cord results in aberrant axonal guidance phenotypes. Our data provide evidence of a new signaling mechanism that couples chemotropic Netrin-1/DCC axonal guidance and Sytx1/TI-VAMP SNARE proteins regulating membrane turnover and exocytosis.


Second messenger modulation of electrotonic coupling between region CA3 pyramidal cell axons in the rat hippocampus.
Gap junction coupling between hippocampal cell axons has been implicated in high frequency oscillations. We used antidromic activation of region CA3 from the fimbria to test the hypothesis that, if gap junctions exist between CA3 pyramidal cell axons, they should cause cross-talk between cells. Agents known to open gap junctions, including 8-Br-cAMP and forskolin (analogue and activator of the cAMP 2nd messenger system respectively) augmented the antidromic population spike and uncovered fast oscillations in the extracellular field. Increasing 2nd messenger concentration reduced the threshold stimulation for antidromic triggering of action potentials, suggesting an improved capability to conduct the electrical impulse retrogradely to the soma. Our studies support the existence of gap junction coupling between CA3 pyramidal cell axons in the fimbria that can be acutely modulated by 2nd messengers.


S-adenosyl-l-methionine (SAMe), cannabidiol (CBD), and kratom in psychiatric disorders: Clinical and mechanistic considerations.
Given the limitations of prescription antidepressants, many individuals have turned to natural remedies for the management of their mood disorders. We review three selected natural remedies that may be of potential use as treatments for depressive disorders and other psychiatric or neurological conditions. The best studied and best supported of these three remedies is S-adenosyl-l-methionine (SAMe), a methyl donor with a wide range of physiological functions in the human organism. With the increasing legalization of cannabis-related products, cannabidiol (CBD) has gained popularity for various potential indications and has even obtained approval in the United States and Canada for certain neurological conditions. Kratom, while potentially useful for certain individuals with psychiatric disorders, is perhaps the most controversial of the three remedies, in view of its greater potential for abuse and dependence. For each remedy, we will review indications, doses and delivery systems, potential anti-inflammatory and immunomodulatory action, adverse effects, and will provide recommendations for clinicians who may be considering prescribing these remedies in their practice.


Country-Specific vs. Common Birthweight-for-Gestational Age References to Identify Small for Gestational Age Infants Born at 24-28 weeks: An International Study.
Controversy exists as to whether birthweight-for-gestational age references used to classify infants as small for gestational age (SGA) should be country specific or based on an international (common) standard. We examined whether different birthweight-for-gestational age references affected the association of SGA with adverse outcomes among very preterm neonates. Singleton infants (n = 23 788) of 24(0) -28(6) weeks' gestational age in nine high-resource countries were classified as SGA (<10th centile) using common and country-specific references based on birthweight and estimated fetal weight (EFW). For each reference, the adjusted relative risk (aRR) for the association of SGA with composite outcome of mortality or major morbidity was estimated. The percentage of infants classified as SGA differed slightly for common compared with country specific for birthweight references [9.9% (95% CI 9.5, 10.2) vs. 11.1% (95% CI 10.7, 11.5)] and for EFW references [28.6% (95% CI 28.0, 29.2) vs. 24.6% (95% CI 24.1, 25.2)]. The association of SGA with the composite outcome was similar when using common or country-specific references for the total sample for birthweight [aRRs 1.47 (95% CI 1.43, 1.51) and 1.48 (95% CI 1.44, 1.53) respectively] and for EFW references [aRRs 1.35 (95% CI 1.31, 1.38) and 1.39 (95% CI 1.35, 1.43) respectively]. Small for gestational age is associated with higher mortality and morbidity in infants born <29 weeks' gestational age. Although common and country-specific birthweight/EFW references identified slightly different proportions of SGA infants, the risk of the composite outcome was comparable.


Environmental osmolality influences sperm motility activation in an anuran amphibian.
Evolutionary theory predicts that selection will favour sperm traits that maximize fertilization success in local fertilization environments. In externally fertilizing species, osmolality of the fertilization medium is known to play a critical role in activating sperm motility, but there remains limited evidence for adaptive responses to local osmotic environments. In this study, we used a split-sample experimental design and computer-assisted sperm analysis to (i) determine the optimal medium osmolality for sperm activation (% sperm motility and sperm velocity) in male common eastern froglets (Crinia signifera), (ii) test for among-population variation in percentage sperm motility and sperm velocity at various activation-medium osmolalities and (iii) test for among-population covariation between sperm performance and environmental osmolality. Frogs were obtained from nine populations that differed in environmental osmolality, and sperm samples of males from different populations were subjected to a range of activation-medium osmolalities. Percentage sperm motility was optimal between 10 and 50 mOsm kg(-1) , and sperm velocity was optimal between 10 and 100 mOsm kg(-1) , indicating that C. signifera has evolved sperm that can function across a broad range of osmolalities. As predicted, there was significant among-population variation in sperm performance. Furthermore, there was a significant interaction between activation-medium osmolality and environmental osmolality, indicating that frogs from populations with higher environmental osmolality produced sperm that performed better at higher osmolalities in vitro. This finding may reflect phenotypic plasticity in sperm functioning, or genetic divergence resulting from spatial variation in the strength of directional selection. Both of these explanations are consistent with evolutionary theory, providing some of the first empirical evidence that local osmotic environments can favour adaptive sperm motility responses in species that use an external mode of fertilization.


Phenotype of recovering lymphoid cell populations after marrow transplantation.
Four patients who received bone marrow transplants were studied sequentially during the posttransplant period to define the pattern of recovering lymphoid cell types. Three patients received T cell-depleted, HLA-matched marrow, and one received untreated marrow from an identical twin. Blood lymphoid cells were labeled with 25 different pairs of monoclonal antibodies. In each sample, one antibody was conjugated to fluorescein and one to phycoerythrin, thus allowing simultaneous assessment of the expression of the two markers using the fluorescence activated cell sorter. A total of 14 antibodies were used, routinely including HLE, Leu-M3, Leu-4, Leu-1, Leu-5, Leu-9, Leu-6, Leu-2, Leu-3, HLA-DR, Leu-7, Leu-11, Leu-15, and Leu-12. Other antibodies were used to further define some populations. This study has allowed us to define six distinct cell types that have appeared in all four patients by day 90 posttransplantation, and which account for 90-100% of all circulating lymphoid cells. These cell types are (a) T helper cells expressing Leu-1, Leu-4, Leu-9, Leu-5, Leu-3, and variable amounts of HLA-DR; (b) T suppressor cells expressing Leu-1, Leu-4, Leu-9, Leu-5, Leu-2, and variable amounts of HLA-DR; (c) B cells expressing Leu-12, B1, HLA-DR, IgD, and IgM, but none of the T cell antigens; (d) an unusual B cell phenotype (Leu-1 B) expressing all of the B cell markers, and also having low amounts of Leu-1, but none of the other T cell antigens; (e) natural killer (NK) cells expressing Leu-11, Leu-15, Leu-5 but none of the other T cell or B cell markers; (f) NK cells expressing Leu-11, Leu-15, Leu-5, and low levels of Leu-2. Both NK types also express Leu-7 on some, but not all cells. The relative frequencies of these cell types varied among the patients and with time, but the striking findings were the presence of relatively few mature T cells, large numbers of NK cells, and the preponderance of the unusual Leu-1 B cell over conventional B cells in all three patients who developed B cells. Sorting experiments confirmed the NK activity of the major NK cell phenotypes, and DNA analysis confirmed that all of the cells studied were of donor origin. In addition, analysis of Ig genes in one patient showed that the Leu-1 B cells were not clonally rearranged.(ABSTRACT TRUNCATED AT 400 WORDS)


Distribution pattern of Plasmodium falciparum chloroquine transporter (pfcrt) gene haplotypes in Sri Lanka 1996-2006.
Widespread antimalarial resistance has been a barrier to malaria elimination efforts in Sri Lanka. Analysis of genetic markers in historic parasites may uncover trends in the spread of resistance. We examined the frequency of Plasmodium falciparum chloroquine transporter (pfcrt; codons 72-76) haplotypes in Sri Lanka in 1996-1998 and 2004-2006 using a high-resolution melting assay. Among 59 samples from 1996 to 1998, we detected the SVMNT (86%), CVMNK (10%), and CVIET (2%) haplotypes, with a positive trend in SVMNT and a negative trend in CVMNK frequency (P = 0.004) over time. Among 24 samples from 2004 to 2006, we observed only the SVMNT haplotype. This finding indicates selection for the SVMNT haplotype over time and its possible fixation in the population.


Disruption of Coronin 1 Signaling in T Cells Promotes Allograft Tolerance while Maintaining Anti-Pathogen Immunity.
The ability of the immune system to discriminate self from non-self is essential for eradicating microbial pathogens but is also responsible for allograft rejection. Whether it is possible to selectively suppress alloresponses while maintaining anti-pathogen immunity remains unknown. We found that mice deficient in coronin 1, a regulator of naive T cell homeostasis, fully retained allografts while maintaining T cell-specific responses against microbial pathogens. Mechanistically, coronin 1-deficiency increased cyclic adenosine monophosphate (cAMP) concentrations to suppress allo-specific T cell responses. Costimulation induced on microbe-infected antigen presenting cells was able to overcome cAMP-mediated immunosuppression to maintain anti-pathogen immunity. In vivo pharmacological modulation of this pathway or a prior transfer of coronin 1-deficient T cells actively suppressed allograft rejection. These results define a coronin 1-dependent regulatory axis in T cells important for allograft rejection and suggest that modulation of this pathway may be a promising approach to achieve long-term acceptance of mismatched allografts.


Self-assembly from the gas-phase: design and implementation of small-molecule chromophore precursors with large nonlinear optical responses.
Efficiently organizing molecular nonlinear optical (NLO) chromophores having large first-order hyperpolarizabilities (beta) into acentric microstructures for electro-optic (EO) applications represents a significant materials synthesis and processing challenge, in part due to interchromophore dipolar interactions that promote centrosymmetric organization. Here we report the computational modeling, synthesis, and characterization of a series of eight heteroaromatic organic chromophores, designed to self-organize from the vapor phase via directed hydrogen-bond networks, into acentric thin films. Introduction of alpha,omega-donor-acceptor hydrogen-bonding substituents along the molecular long axes tunes properties such as hyperpolarizability, volatility, thermal stability, film-forming properties, and macroscopic NLO response (chi((2))). DFT-level molecular modeling, INDO/S optical property analysis, and sum-overstates computation indicate that molecular-core fluorination and hydrogen-bond donor incorporation can increase beta(vec) up to 40x versus that of typical fluorine-free chromophores. Furthermore, inclusion of sterically induced biphenyl conjugative decoupling between chromophore pi-donor substituents and the hydrogen-bonding donor sites increases beta by approximately 50%. Experimental thin-film second harmonic generation (SHG) spectroscopy confirms these trends in calculated responses, with chi((2)) increasing 7.5x upon chromophore core fluorination and 15x with hydrogen-bonding donor substitution, thereby achieving macroscopic responses as high as 302 pm/V at omega(o) = 1064 nm. In addition to response trends, cluster calculations also reveal linear additivity in beta(vec) with catenation for all benzoic acid-containing chromophores up to longitudinally aligned trimers. Linear scaling of SHG response with film thickness is observed for benzoic acid-containing chromophores up to 1.0 microm film thickness.


The high fidelity and unique error signature of human DNA polymerase epsilon.
Bulk replicative DNA synthesis in eukaryotes is highly accurate and efficient, primarily because of two DNA polymerases (Pols): Pols δ and ε. The high fidelity of these enzymes is due to their intrinsic base selectivity and proofreading exonuclease activity which, when coupled with post-replication mismatch repair, helps to maintain human mutation rates at less than one mutation per genome duplication. Conditions that reduce polymerase fidelity result in increased mutagenesis and can lead to cancer in mice. Whereas yeast Pol ε has been well characterized, human Pol ε remains poorly understood. Here, we present the first report on the fidelity of human Pol ε. We find that human Pol ε carries out DNA synthesis with high fidelity, even in the absence of its 3'→5' exonucleolytic proofreading and is significantly more accurate than yeast Pol ε. Though its spectrum of errors is similar to that of yeast Pol ε, there are several notable exceptions. These include a preference of the human enzyme for T→A over A→T transversions. As compared with other replicative DNA polymerases, human Pol ε is particularly accurate when copying homonucleotide runs of 4-5 bases. The base pair substitution specificity and high fidelity for frameshift errors observed for human Pol ε are distinct from the errors made by human Pol δ.


The impact of low-dose insulin on peripheral nerve insulin receptor signaling in streptozotocin-induced diabetic rats.
The precise mechanisms of the neuroprotective effects of insulin in streptozotocin (STZ)-induced diabetic animals remain unknown, but altered peripheral nerve insulin receptor signaling due to insulin deficiency might be one cause. Diabetes was induced in 10-week-old, male Wistar rats by injecting them with STZ (45 mg/kg). They were assigned to one group that received half of an insulin implant (∼1 U/day; I-group, n = 11) or another that remained untreated (U-group, n = 10) for 6 weeks. The controls were age- and sex-matched, non-diabetic Wistar rats (C-group, n = 12). Low-dose insulin did not change haemoglobin A1c, which increased by 136% in the U-group compared with the C-group. Thermal hypoalgesia and mechanical hyperalgesia developed in the U-group, but not in the I-group. Sensory and motor nerve conduction velocities decreased in the U-group, whereas sensory nerve conduction velocity increased by 7% (p = 0.0351) in the I-group compared with the U-group. Western blots showed unaltered total insulin receptor (IR), but a 31% decrease and 3.1- and 4.0-fold increases in phosphorylated IR, p44, and p42 MAPK protein levels, respectively, in sciatic nerves from the U-group compared with the C-group. Phosphorylated p44/42 MAPK protein decreased to control levels in the I-group (p<0.0001). Low-dose insulin deactivated p44/42 MAPK and ameliorated peripheral sensory nerve dysfunction in rats with STZ-induced diabetes. These findings support the notion that insulin deficiency per se introduces impaired insulin receptor signaling in type 1 diabetic neuropathy.


Cross-Cultural Adaptation of the Social Vulnerability Index for Use in the Dutch Context.
Being able to identify socially frail older adults is essential for designing interventions and policy and for the prediction of health outcomes, both on the level of individual older adults and of the population. The aim of the present study was to adapt the Social Vulnerability Index (SVI) to the Dutch language and culture for those purposes. A systematic cross-cultural adaptation of the initial Social Vulnerability Index was performed following five steps: initial translation, synthesis of translations, back translation, a Delphi procedure, and a test for face validity and feasibility. The main result of this study is a face-valid 32 item Dutch version of the Social Vulnerability Index (SVI-D) that is feasible in health care and social care settings. The SVI-D is a useful index to measure social frailty in Dutch-language countries and offers a broad, holistic quantification of older people's social circumstances related to the risk of adverse health outcomes.


Are yellow sticky traps an effective method for control of sweetpotato whitefly, Bemisia tabaci, in the greenhouse or field?
Yellow sticky traps are a common method for monitoring many pests, but it has not been shown whether they could be used as a control method. In this study the impact of yellow sticky traps on the population dynamics of the sweetpotato whitefly, Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae) was determined in the greenhouse and field. In the greenhouse, yellow sticky traps significantly suppressed the population increase of adult and immature whiteflies. The whitefly densities in the greenhouse with traps were significantly lower than the greenhouse without traps. In the field, traps did not have a significant impact on the population dynamics of adult and immature whiteflies. The densities in fields with traps were very similar to fields without traps. These results suggest that yellow sticky traps can be used as an effective method for the control of whiteflies in the greenhouse, but not in the field. This information will prove useful for the effective management of whiteflies in greenhouses.


Variation in patient management and outcomes for acute coronary syndromes in Latin America and North America: results from the Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial.
Although more than 9500 patients have been enrolled in major clinical trials in Latin America, practice patterns in this region have rarely been examined. We sought to compare characteristics, resource utilization, and outcomes of patients treated for acute coronary syndromes in Latin America with those in North America. The Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Theraphy Trial (PURSUIT) enrolled 10,948 patients with non-ST-segment elevation acute coronary syndromes, including 585 in Latin America and 4358 in North America. We analyzed regional differences in patient groups, treatment patterns, and outcomes and used logistic regression analysis to identify association of enrollment region and survival. For patients in Latin America, the length of hospital stay was significantly longer (10 [7, 15] days vs 6 [4, 9], P <.001). Angiograms, angioplasty, and bypass surgery were significantly less common in Latin America (46.2%, 17.6%, and 11.3% vs 79.4%, 33.6%, and 19.4%, P <.001). Thirty-day death/myocardial infarction was not significantly higher, although mortality alone was significantly higher (6.8% vs 3.1%, P <.001). After adjustment for baseline characteristics, enrollment in Latin America remained an independent predictor for death at 30 days (odds ratio [OR] [95% confidence interval (CI)] 2.42 [1.60-3.67]) and persisted at 6 months (OR [95% CI] 2.5 [1.8-3.4]). Latin American patients treated for acute coronary syndromes were managed less invasively and were twice as likely as their North American counterparts to die within 6 months. This mortality difference was not explained by imbalances in baseline risk.


Cognitive hypnotherapy for psychological management of depression in palliative care.
The prevalence of psychiatric disorders in palliative care is well documented, yet they often remain undetected and untreated, adding further to the burden of suffering on patients who are already facing severe physical and psychosocial problems. This article will focus on depression as it represents one of the most common psychiatric disorders treated by psychiatrists and psychotherapists in palliative care. Although depression in palliative care can be treated successfully with antidepressant medication and psychotherapy, a significant number of depressives do not respond to either medication or existing psychotherapies. This is not surprising considering depression is a complex disorder. Moreover, the presentation of depression in palliative care is compounded by the severity of the underlying medical conditions. It is thus important for clinicians to continue to develop more effective treatments for depression in palliative care. This article describes cognitive hypnotherapy (CH), an evidence-based multimodal treatment for depression which can be applied to a wide range of depressed patients in palliative care. CH, however, does not represent a finished product; it is a work in progress to be empirically validated and refined by advances in cancer and clinical depression.


Diarrhoea episodes and treatment-seeking behaviour in a slum area of North Jakarta, Indonesia.
Visits to household during a census in an impoverished area of north Jakarta were used for exploring the four-week prevalence of diarrhoea, factors associated with episodes of diarrhoea, and the patterns of healthcare use. For 160,261 urban slum-dwellers, information was collected on the socioeconomic status of the household and on diarrhoea episodes of individual household residents in the preceding four weeks. In households with a reported case of diarrhoea, the household head was asked which form of healthcare was used first. In total, 8,074 individuals (5%)--13% of children aged less than five years and 4% of adults--had a diarrhoea episode in the preceding four weeks. The two strongest factors associated with a history of diarrhoea were a diarrhoea episode in another household member in the four weeks preceding the interview (adjusted odds ratio [OR] 11.1; 95% confidence interval [CI] 10.4-11.8) and age less than five years (adjusted OR 3.4; 95% CI 3.2-3.5). Of the 8,074 diarrhoea cases, 1,969 (25%) treated themselves, 1,822 (23%) visited a public-health centre (PHC), 1,462 (18%) visited a private practitioner or a private clinic, 1,318 (16%) presented at a hospital, 753 (9%) bought drugs from a drug vendor, and 750 (9%) used other healthcare providers, such as belian (traditional healers). Children with diarrhoea were most often brought to a PHC, a private clinic, or a hospital for treatment. Compared to children, adults with diarrhoea were more likely to treat themselves. Individuals from households in the lowest-income group were significantly more likely to attend a PHC for treatment of diarrhoea compared to individuals from households in the middle- and higher-income groups.


Investigation of ternary metal dodecaborides (M1M2M3)B12 (M1, M2 and M3 = Zr, Y, Hf and Gd).
Samples of metal borides with a nominal composition of ((M1)(1-x-z)(M2)(x)(M3)(z)) : 20B (M1, M2 and M3 = Zr, Y, Hf and Gd) were prepared by arc-melting and studied for phase composition (using powder X-ray diffraction (PXRD) and energy dispersive X-ray spectroscopy (EDS)) and mechanical properties (Vickers hardness). Ternary metal dodecaboride phases were successfully synthesized for the majority of compositions, including stabilization of two high-pressure (6.5 GPa) phases (cubic-UB12 structure), HfB12 and GdB12, in (Zr1-x-zHfxGdz) : 20B and (Y1-x-zHfxGdz) : 20B nominal alloy compositions. Unit cell refinement for the samples showed solid solution formation in most cases. Vickers hardness measurements indicated that most samples possess enhanced hardness in comparison to their parent phases, with the alloy (Zr0.50Y0.25Gd0.25) : 20B having a hardness of 46.9 ± 2.4 GPa compared to 41.3 ± 1.1 and 41.6 ± 1.3 GPa for alloy compositions of 1.0 Zr : 20B and 1.0 Y : 20B, respectively, at 0.49 N of applied load. Using the data from this manuscript as well as previous work, pseudo-ternary phase diagrams (at a constant boron content) have been constructed.


Perceptions of Aboriginal and Torres Strait Islander Australians toward cardiovascular primary prevention programs: A qualitative systematic review.
To synthesize the best available qualitative evidence on the perceptions of Aboriginal and Torres Strait Islander Australians (hereafter, respectfully referred to as Indigenous Australians) toward participation in cardiovascular primary prevention programs. In 2017, cardiovascular disease was the leading cause of premature mortality in Indigenous Australians, accounting for 11.5% of all deaths. Health risk behaviors such as smoking, physical inactivity, poor nutrition, and obesity largely contribute to this burden of disease. A search using MEDLINE, CINAHL, EMBASE, PubMed, Google Scholar, MedNar, ProQuest and Index to Theses for published and unpublished studies was conducted in January 2020. The methodological quality of the included studies was independently assessed by two reviewers using the Joanna Briggs Institute (JBI) critical appraisal tool. Data extraction and meta-aggregation were conducted in accordance with JBI methodology. Eleven studies were included. Three synthesized findings were developed (a) social and community support affect participants' experiences of prevention programs; (b) structural drivers and social determinants influence Indigenous Australians experiences and participation in prevention programs and health risk behavioral change; and (c) a personal desire to change behaviors and participate in prevention programs requires development of knowledge regarding healthy lifestyles and creation of new social norms. Indigenous Australians participation in primary prevention for cardiovascular risk factors and adoption of a healthy lifestyle are influenced by social support, social determinants, and personal desire. Future programs need to tackle the structural drivers and facilitate a supportive environment to assist in health risk behavior change.


An assessment of the Irish population for large-scale genetic mapping studies involving epilepsy and other complex diseases.
The recent completion of the International HapMap Project has rapidly advanced our understanding of linkage disequilibrium (LD) in the human genome. Today, tagging SNPs (tSNPs) can be quickly and easily selected and consequently HapMap data are regularly applied to both small- and large-scale genetic mapping studies. However, to correctly interpret the application of HapMap-derived tSNPs in a genetic mapping study, an understanding of how well HapMap data represents LD in the study population is critical. The Irish population had not previously been characterised in this way. Here, we do so using a set of 4424 SNPs selected from 279 candidate genes for epilepsy genotyped across 1118 healthy individuals from the Irish, British, Finnish and Australian populations. By considering the Irish population alongside surrounding European populations, our results confirm that the HapMap European-derived population accurately estimates patterning of LD in European descent populations. The Irish population appears notably well matched to the European HapMap population, and is markedly similar to the neighbouring British population. Although we were unable to detect significant substructure within the Irish population (a favourable result for genetic mapping), methods for controlling stratification should always be incorporated. This analysis therefore confirms that the genetic architecture of the Irish population is well suited to the study of complex traits and that tSNPs selected using the HapMap data can be confidently applied to the Irish population.


Elements including metals in the atomizer and aerosol of disposable electronic cigarettes and electronic hookahs.
Our purpose was to quantify 36 inorganic chemical elements in aerosols from disposable electronic cigarettes (ECs) and electronic hookahs (EHs), examine the effect of puffing topography on elements in aerosols, and identify the source of the elements. Thirty-six inorganic chemical elements and their concentrations in EC/EH aerosols were determined using inductively coupled plasma optical emission spectroscopy, and their source was identified by analyzing disassembled atomizers using scanning electron microscopy and energy dispersive X-ray spectroscopy. Of 36 elements screened, 35 were detected in EC/EH aerosols, while only 15 were detected in conventional tobacco smoke. Some elements/metals were present in significantly higher concentrations in EC/EH aerosol than in cigarette smoke. Concentrations of particular elements/metals within EC/EH brands were sometimes variable. Aerosols generated at low and high air-flow rates produced the same pattern of elements, although the total element concentration decreased at the higher air flow rate. The relative amount of elements in the first and last 60 puffs was generally different. Silicon was the dominant element in aerosols from all EC/EH brands and in cigarette smoke. The elements appeared to come from the filament (nickel, chromium), thick wire (copper coated with silver), brass clamp (copper, zinc), solder joints (tin, lead), and wick and sheath (silicon, oxygen, calcium, magnesium, aluminum). Lead was identified in the solder and aerosol of two brands of EHs (up to 0.165 μg/10 puffs). These data show that EC/EH aerosols contain a mixture of elements, including heavy metals, with concentrations often significantly higher than in conventional cigarette smoke. While the health effects of inhaling mixtures of heated metals is currently not known, these data will be valuable in future risk assessments involving EC/EH elements/metals.


Cushioning and lateral stability functions of cloth sport shoes.
In this study, we evaluated the protective functions of cloth sport shoes, including cushioning and lateral stability. Twelve male students participated in the study (mean +/- s: age 12.7 +/- 0.4 years, mass 40.7 +/- 5.9kg, height 1.50 +/- 0.04m). Cloth sport shoes, running shoes, basketball shoes, crosstraining shoes, and barefoot conditions were investigated in random sequence. Human pendulum and cutting movement tests were used to assess cushioning performance and lateral stability, respectively. For cushioning, the running shoes (2.06 body weight, BW) performed the best, while the cross-training shoes (2.30 BW) and the basketball shoes (2.37 BW) both performed better than the cloth sport shoes (2.55 BW) and going barefoot (2.63 BW). For the lateral stability test, range of inversion--eversion was found to be from 3.6 to 4.9 degrees, which was far less than that for adult participants (> 20 degrees). No significant differences were found between conditions. All conditions showed prolonged durations from foot-strike to maximum inversion (66-95 ms), which was less vigorous than that for adult participants (< 40 ms) and was unlikely to evoke intrinsic stability failure. In conclusion, the cloth sport shoe showed inferior cushioning capability but the same lateral stability as the other sports shoes for children.


Array illuminator with arbitrary fan-out.
An approach for designing Talbot array illuminators that produce quasi-arbitrary numbers of spots and quasi-arbitrary distributions of these spots in the output plane is proposed. The approach consists in combining elementary Talbot array illuminators. In addition to the quasi-arbitrary topology of the output spots, the resulting compound array illuminator shows several advantages such as its ability to be used for both coherent and incoherent imaging. Compared with elementary array illuminators, the compound illuminator does not add any specific technological complication.


Protection against peroxynitrite by cocoa polyphenol oligomers.
Flavonoids, natural plant constituents, protect against peroxynitrite and can thereby play a role in defense against this mediator of inflammation. Procyanidin oligomers of different size (monomer through nonamer), isolated from the seeds of Theobroma cacao, were examined for their ability to protect against peroxynitrite-dependent oxidation of dihydrorhodamine 123 and nitration of tyrosine. By molarity, oligomers were more effective than the monomeric epicatechin; the tetramer was particularly efficient at protecting against oxidation and nitration reactions. These results suggest that epicatechin oligomers found in cocoa powder and chocolate may be a potent dietary source for defense against peroxynitrite.


Stem cell-related therapies for vascular diseases.
The therapeutic potential of 'adult' or at least non-embryonic stem cells and their progeny has developed gradually over the past half century as a consequence of the wealth of knowledge derived from stem cell research. Translational research coupled with clinical trials and derived from basic research has led the way to the clinic. This commenced with the use of haematopoietic stem cell transplantation (HSCT), to treat haematological malignancies, to be followed by the most recent clinical trials to treat a variety of coronary and peripheral artery diseases. Stem cells and their progeny isolated from bone marrow or blood appear to exert an ameliorating effect in certain vascular disorders. Although promising, some of these treatments remain controversial and further research and, where indicated, appropriately powered trials are required to confirm the safety and determine the efficacy of these novel therapies.


Proton therapy for nasopharyngeal carcinoma.
The treatment of nasopharyngeal carcinoma (NPC) has traditionally included a multimodality approach including radiotherapy (RT) and systemic chemotherapy. RT has long been favored as the mainstay of local treatment for disease in this challenging anatomic location owing to the morbidity of extensive surgical resection in the nasopharynx. However, NPC presents a unique treatment challenge for radiation oncologists because such tumors typically involve complex anatomic structures near several critical organ structures such as the brainstem, spinal cord, temporal lobes, salivary glands, cochleae, oral cavity, mandible and optic structures. Thus, radiation is not without toxicity, and critical organs in these areas clearly benefit from the use of conformal and precise treatment delivery. The unique physical properties of proton radiotherapy (PRT) make it especially well-suited for treating tumors in this anatomically complex area and offer promising potential for acute and chronic toxicity reduction while maintaining excellent disease control.


Effects of high-dose gamma-vinyl GABA (vigabatrin) administration on visual and somatosensory evoked potentials in dogs.
gamma-Vinyl GABA (GVG, vigabatrin) is a GABA transaminase-inhibiting antiepileptic agent. In dogs, chronic GVG administration produces reversible microvacuolation (intramyelinic edema) in discrete brain regions and slowing in central afferent transmission as measured by somatosensory evoked potentials (SEPs). Because this microvacuolation is especially prominent in the optic tract, this study tested the sensitivity of visual evoked potentials (VEPs) to GVG-induced changes in conduction. We also replicated the earlier SEP findings. Eight beagles received daily oral vigabatrin at the maximum tolerated dose (300 mg/kg/day); four were placebo controls. Cortical VEPs and SEPs were recorded using scalp needle electrodes at baseline and every 2 weeks throughout treatment. One treatment dog died at 2 weeks. The remainder showed an increase in central latencies beginning at 6 weeks, attaining significance (p < 0.05) at 8 and 10 weeks for SEPs and VEPs, respectively. No changes occurred in peripheral or spinal conduction in treated dogs, or in any measure in control dogs. Three GVG and two control dogs were followed after drug was withdrawn; both VEP and SEP measures returned to baseline values within 5 weeks. These findings support the use of VEPs and SEPs to monitor patients receiving vigabatrin therapy.


The impact of HIV-associated neuropsychological impairment on everyday functioning.
HIV-1 infection can be associated with neuropsychological (NP) deficits ranging from subtle to severe. The purpose of this study was to evaluate the functional, or "real-world" impact of HIV-associated NP impairment in a group of 267 HIV-infected participants. All participants received comprehensive NP, neuromedical, and standardized functional evaluations that included laboratory measures of shopping, cooking, financial management, medication management and vocational abilities. Compared to NP-normal participants, those with NP impairment performed significantly worse on all laboratory measures of everyday functioning. Multivariate analyses revealed that the NP ability domains of Abstraction/Executive Function, Learning, Attention/Working Memory and Verbal abilities most strongly and consistently predicted failures on the functional battery. Both NP impairment and impairment on the functional battery were significantly associated with subjective experiences of cognitive difficulties, as well as unemployment and increased dependence in activities of daily living; multivariate prediction models that also considered depressed mood and biological measures of disease progression revealed that impairment on the functional battery and depression were the only unique predictors of all three indicators of "real-world" functioning. The current results add to growing evidence concerning the clinical significance of HIV-associated NP impairment. Objective, laboratory based functional measures, such as those used here, may compliment NP testing in future studies directed at understanding the impact on life quality of central nervous system disorders and their treatments. Finally, there is a need for additional research investigating the apparently independent effect of depression on level of everyday functioning in HIV infected persons.


Depletion of RAD17 sensitizes pancreatic cancer cells to gemcitabine.
Chemotherapy of advanced pancreatic cancer has mainly been gemcitabine-based for the past 15 years, with only limited effect. Recently, combination therapy that also targets checkpoint kinase 1 (CHK1) has become an attractive option. The central role of CHK1 in many DNA-damage response pathways, however, may result in undesired cytotoxicity in normal cells, causing side effects. We were searching for other target molecules of similar function that may be more specific and thus better suited for combination therapy. To this end a negative selection RNAi screen was performed in cell lines with small hairpin RNA molecules targeting over 10,000 genes. Genes that were found to be synthetically lethal with gemcitabine and whose proteins act upstream of CHK1 were characterised in more detail. In particular, the inhibition of RAD17 potentiated gemcitabine cytotoxicity in the pancreatic cancer cell lines BxPC-3 and MiaPaca-2 and in the primary cell line JoPaca-1 that closely resembles primary tumour tissue. Further analysis showed that the synergistic effect of RAD17 knockdown and gemcitabine leads to forced mitotic entry of cells arrested in S phase by gemcitabine treatment, resulting in asymmetric DNA distribution during anaphase followed by DNA fragmentation and finally cell death by mitotic catastrophe. Our data suggest RAD17 as a novel target protein for gemcitabine combination therapy supplementing or complementing inhibition of CHK1. In contrast to CHK1, RAD17 knockdown by itself does not lead to abnormal DNA segregation, suggesting a more specific action.


Follicular competition in cows: the selection of dominant follicles as a synergistic effect.
The reproductive cycle of mono-ovulatory species such as cows or humans is known to show two or more waves of follicular growth and decline between two successive ovulations. Within each wave, there is one dominant follicle escorted by subordinate follicles of varying number. Under the surge of the luteinizing hormone a growing dominant follicle ovulates. Rarely the number of ovulating follicles exceeds one. In the biological literature, the change of hormonal concentrations and individually varying numbers of follicular receptors are made responsible for the selection of exactly one dominant follicle, yet a clear cause has not been identified. In this paper, we suggest a synergistic explanation based on competition, formulated by a parsimoniously defined system of ordinary differential equations (ODEs) that quantifies the time evolution of multiple follicles and their competitive interaction during one wave. Not discriminating between follicles, growth and decline are given by fixed rates. Competition is introduced via a growth-suppressing term, equally supported by all follicles. We prove that the number of dominant follicles is determined exclusively by the ratio of follicular growth and competition. This number turns out to be independent of the number of subordinate follicles. The asymptotic behavior of the corresponding dynamical system is investigated rigorously, where we demonstrate that the [Formula: see text]-limit set only contains fixed points. When also including follicular decline, our ODEs perfectly resemble ultrasound data of bovine follicles. Implications for the involved but not explicitly modeled hormones are discussed.


Increase in the Regional Cerebral Blood Flow following Waon Therapy in Patients with Chronic Fatigue Syndrome: A Pilot Study.
Objective Chronic fatigue syndrome (CFS) is a complex disorder, with no consensus on therapeutic options. However, Waon therapy has been reported to be an effective treatment. The purpose of this study was to evaluate changes in the cerebral blood flow (CBF) before and after Waon therapy in CFS patients and to investigate the correlation between such changes and the therapeutic efficacy of Waon therapy. Methods Eleven patients (2 men and 9 women, mean age 27 years old) diagnosed with CFS participated in the study. The disease duration was 8-129 months, and the performance status was 5-8 (on a scale of 0-9). All patients underwent CBF scintigraphy using brain single-photon emission computed tomography (SPECT) with technetium-99m ethyl cysteinate dimer (99mTc-ECD) before and after Waon therapy. CBF changes after Waon therapy were evaluated using a statistical analysis of imaging data, which was performed with a statistical parametric mapping software program (SPM5). Results Waon therapy reduced symptoms in all 11 patients. We also observed an increase in the CBF within the prefrontal region, orbitofrontal region, and right temporal lobe. These results indicated that an improvement in clinical symptoms was linked to an increase in the CBF. Conclusion The results indicated abnormalities of the cerebral function in the prefrontal region, orbitofrontal region, and right temporal lobe in CFS patients and that Waon therapy improved the cerebral function and symptoms in CFS patients by increasing the regional CBF. To our knowledge, this is the first report to clarify the CBF changes in CFS patients before and after Waon therapy.


Transport via SLC5A8 (SMCT1) is obligatory for 2-oxothiazolidine-4-carboxylate to enhance glutathione production in retinal pigment epithelial cells.
To evaluate the role of SLC5A8 in the transport of 2-oxothiazolidine-4-carboxylate (OTC) and to determine whether OTC augments glutathione production in RPE cells, thereby providing protection against oxidative stress. SLC5A8-mediated transport of OTC was monitored in Xenopus laevis oocytes by electrophysiological means. Saturation kinetics, Na(+)-activation kinetics, and inhibition by ibuprofen were analyzed by monitoring OTC-induced currents as a measure of transport activity. Oxidative stress was induced in ARPE-19 cells and primary RPE cells isolated from wild type and Slc5a8(-/-) mouse retinas using H(2)O(2), and the effects of OTC on cell death and intracellular glutathione concentration were examined. Heterologous expression of human SLC5A8 in X. laevis oocytes induced Na(+)-dependent inward currents in the presence of OTC under voltage-clamp conditions. The transport of OTC via SLC5A8 was saturable, with a K(t) of 104 ± 3 μM. The Na(+)-activation kinetics was sigmoidal with a Hill coefficient of 1.9 ± 0.1, suggesting involvement of two Na(+) in the activation process. Ibuprofen, a blocker of SLC5A8, inhibited SLC5A8-mediated OTC transport; the concentration necessary for half-maximal inhibition was 17 ± 1 μM. OTC increased glutathione levels and protected ARPE-19 and primary RPE cells isolated from wild type mouse retinas from H(2)O(2)-induced cell death. These effects were abolished in primary RPE isolated from Slc5a8(-/-) mouse retinas. OTC is a transportable substrate for SLC5A8. OTC augments glutathione production in RPE cells, thereby protecting them from oxidative damage. Transport via SLC5A8 is obligatory for this process.


Evaluation of magnetic resonance imaging techniques in the equine digit.
An anatomic study of the equine digit using magnetic resonance imaging (MRI) was performed. Seventeen isolated forelimbs and one hindleg of nine warmblood horses were imaged in transverse, sagittal, and dorsal planes with a 1.5 Tesla magnet using T1-, T2- proton density-weighted spin echo sequences as well as T2 gradient echo sequences. One scan plane in each horse was compared with corresponding anatomic and histologic sections. The best imaging planes to visualize various anatomic structures were determined. Fibrocartilage was visualized in the insertion of the deep digital flexor tendon and the suspensory ligament as well as in the distal sesamoidean ligaments. The correlation of MRI images with anatomic and histologic sections confirmed that all of the anatomic structures in the equine digit could be evaluated in PD and T2 studies.


Live covisualization of competing adeno-associated virus and herpes simplex virus type 1 DNA replication: molecular mechanisms of interaction.
We performed live cell visualization assays to directly assess the interaction between competing adeno-associated virus (AAV) and herpes simplex virus type 1 (HSV-1) DNA replication. Our studies reveal the formation of separate AAV and HSV-1 replication compartments and the inhibition of HSV-1 replication compartment formation in the presence of AAV. AAV Rep is recruited into AAV replication compartments but not into those of HSV-1, while the single-stranded DNA-binding protein HSV-1 ICP8 is recruited into both AAV and HSV-1 replication compartments, although with differential staining patterns. Slot blot analysis of coinfected cells revealed a dose-dependent inhibition of HSV-1 DNA replication by wild-type AAV but not by rep-negative recombinant AAV. Consistent with this, Western blot analysis indicated that wild-type AAV affects the levels of the HSV-1 immediate-early protein ICP4 and the early protein ICP8 only modestly but strongly inhibits the accumulation of the late proteins VP16 and gC. Furthermore, we demonstrate that the presence of Rep in the absence of AAV DNA replication is sufficient for the inhibition of HSV-1. In particular, Rep68/78 proteins severely inhibit the formation of mature HSV-1 replication compartments and lead to the accumulation of ICP8 at sites of cellular DNA synthesis, a phenomenon previously observed in the presence of viral polymerase inhibitors. Taken together, our results suggest that AAV and HSV-1 replicate in separate compartments and that AAV Rep inhibits HSV-1 at the level of DNA replication.


The Rise of Hospitalists: An Opportunity for Clinical Ethics.
Translating ethical theories into clinical practice presents a perennial challenge to educators. While many suggestions have been put forth to bridge the theory-practice gap, none have sufficiently remedied the problem. We believe the ascendance of hospital medicine, as a dominant new force in medical education and patient care, presents a unique opportunity that could redefine the way clinical ethics is taught. The field of hospital medicine in the United States is comprised of more than 50,000 hospitalists-specialists in inpatient medicine-representing the fastest growing subspecialty in the history of medicine, and its members have emerged as a dominant new force around which medical education and patient care pivot. This evolution in medical education presents a unique opportunity for the clinical ethics community. Through their proximity to patients and trainees, hospitalists have the potential to teach medical ethics in real time on the wards, but most hospitalists have not received formal training in clinical ethics. We believe it is time to strengthen the ties between hospital medicine and medical ethics, and in this article we outline how clinical ethicists might collaborate with hospitalists to identify routine issues that do not rise to the level of an "ethics consult," but nonetheless require an intellectual grounding in normative reasoning. We use a clinical vignette to explore how this approach might enhance and broaden the scope of medical education that occurs in the inpatient setting: A patient with an intra-abdominal abscess is admitted to the academic hospitalist teaching service for drainage of the fluid, hemodynamic support, and antimicrobial therapy. During the initial encounter with the hospitalist and his team of medical students and residents, the patient reports night sweats and asks if this symptom could be due to the abscess. How should the hospitalist approach this question?


MRSA nasal carriage patterns and the subsequent risk of conversion between patterns, infection, and death.
Patterns of methicillin-resistant S. aureus (MRSA) nasal carriage over time and across the continuum of care settings are poorly characterized. Knowledge of prevalence rates and outcomes associated with MRSA nasal carriage patterns could help direct infection prevention strategies. The VA integrated health-care system and active surveillance program provides an opportunity to delineate nasal carriage patterns and associated outcomes of death, infection, and conversion in carriage. We conducted a retrospective cohort study including all patients admitted to 5 acute care VA hospitals between 2008-2010 who had nasal MRSA PCR testing within 48 hours of admission and repeat testing within 30 days. The PCR results were used to define a baseline nasal carriage pattern of never, intermittently, or always colonized at 30 days from admission. Follow-up was up to two years and included acute, long-term, and outpatient care visits. Among 18,038 patients, 91.1%, 4.4%, and 4.6% were never, intermittently, or always colonized at the 30-day baseline. Compared to non-colonized patients, those who were persistently colonized had an increased risk of death (HR 2.58; 95% CI 2.18;3.05) and MRSA infection (HR 10.89; 95% CI 8.6;13.7). Being in the non-colonized group at 30 days had a predictive value of 87% for being non-colonized at 1 year. Conversion to MRSA colonized at 6 months occurred in 11.8% of initially non-colonized patients. Age >70 years, long-term care, antibiotic exposure, and diabetes identified >95% of converters. The vast majority of patients are not nasally colonized with MRSA at 30 days from acute hospital admission. Conversion from non-carriage is infrequent and can be risk-stratified. A positive carriage pattern is strongly associated with infection and death. Active surveillance programs in the year following carriage pattern designation could be tailored to focus on non-colonized patients who are at high risk for conversion, reducing universal screening burden.


What Adverse Events and Injuries Are Cited in Anesthesia Malpractice Claims for Nonspine Orthopaedic Surgery?
Malpractice claims that arise during the perioperative care of patients receiving orthopaedic procedures will frequently involve both orthopaedic surgeons and anesthesiologists. The Anesthesia Closed Claims database contains anesthesia malpractice claim data that can be used to investigate patient safety events arising during the care of orthopaedic patients and can provide insight into the medicolegal liability shared by the two specialties. (1) How do orthopaedic anesthetic malpractice claims differ from other anesthesia claims with regard to patient and case characteristics, common events and injuries, and liability profile? (2) What are the characteristics of patients who had neuraxial hematomas after spinal and epidural anesthesia for orthopaedic procedures? (3) What are the characteristics of patients who had orthopaedic anesthesia malpractice claims for central ischemic neurologic injury occurring during shoulder surgery in the beach chair position? (4) What are the characteristics of patients who had malpractice claims for respiratory depression and respiratory arrests in the postoperative period? The Anesthesia Closed Claims Project database was the source of data for this study. This national database derives data from a panel of liability companies (national and regional) and includes closed malpractice claims against anesthesiologists representing > 30% of practicing anesthesiologists in the United States from all types of practice settings (hospital, surgery centers, and offices). Claims for damage to teeth or dentures are not included in the database. Patient characteristics, type of anesthesia, damaging events, outcomes, and liability characteristics of anesthesia malpractice claims for events occurring in the years 2000 to 2013 related to nonspine orthopaedic surgery (n = 475) were compared with claims related to other procedures (n = 1592) with p < 0.05 as the criterion for statistical significance and two-tailed tests. Odds ratios and their 95% confidence intervals were calculated for all comparisons. Three types of claims involving high-impact injuries in patients undergoing nonspine orthopaedic surgery were identified through database query for in-depth descriptive review: neuraxial hematoma (n = 10), central ischemic neurologic injury in the beach chair position (n = 9), and injuries caused by postoperative respiratory depression (n = 23). Nonspine orthopaedic anesthesia malpractice claims were more frequently associated with nerve injuries (125 of 475 [26%], odds ratio [OR] 2.12 [1.66-2.71]) and events arising from the use of regional anesthesia (125 of 475 [26%], OR 6.18 (4.59-8.32) than in malpractice claims in other areas of anesthesia malpractice (230 of 1592 [14%] and 87 of 1592 [6%], respectively, p < 0.001 for both comparisons). Ninety percent (nine of 10) of patients with claims for neuraxial hematomas were receiving anticoagulant medication and all had severe long-term injuries, most with a history of significant delay in diagnosis and treatment after first appearance of signs and symptoms. Central ischemic injuries occurring during orthopaedic surgery in the beach chair position did not occur solely in patients who would have been considered at high risk for ischemic stroke. Patients with malpractice claims for injuries resulting from postoperative respiratory depression events had undergone lower extremity procedures (20 of 23 [87%]) and most events (22 of 23 [96%]) occurred on the day of surgery or the first postoperative day. Nonspine orthopaedic anesthesia malpractice claims more frequently cited nerve injury and events arising from the use of regional anesthesia than other surgical anesthesia malpractice claims. This may reflect the frequency of regional anesthesia in orthopaedic cases rather than increased risk of injury associated with regional techniques. When neuraxial procedures and anticoagulation regimens are used concurrently, care pathways should emphasize clear lines of responsibility for coordination of care and early investigation of any unusual neurologic findings that might indicate neuraxial hematoma. We do not have a good understanding of the factors that render some patients vulnerable to the rare occurrence of intraoperative central ischemic injury in the beach chair position, but providers should carefully calculate cerebral perfusion pressure relative to measured blood pressure for patients in the upright position. Postoperative use of multiple opioids by different concurrent modes of administration warrant special precautions with consideration given to the provision of care in settings with enhanced respiratory monitoring. The limitations of retrospective closed claims database review prevent conclusions regarding causation. Nonetheless, the collection of relatively rare events with substantial clinical detail provides valuable data to generate hypotheses about causation with potential for future study to improve patient safety. Level III, therapeutic study.


Hypoxia induces oxytocin release in the rat.
These studies were undertaken to investigate the impact of hypoxia on the release of oxytocin (OXT) at the median eminence (ME) in adult male rats, and the possible glucocorticoid involvement in modulating this release. Hypoxia was achieved in a hypobaric chamber. The results were as follows: (a) Acute hypoxic stress induced a release of OXT in ME proportional to its intensity and duration. (b) Chronic hypoxia (5-25 days) had no statistically significant influence on the ME level of OXT. (c) After bilateral adrenalectomy (ADX), the levels of OXT in ME were decreased, and there were no further significant changes in these levels when the rats were exposed to hypoxia. (d) The decrease of OXT in ME of ADX rats was partly reversed by replacement with dexamethasone (DEX, i.p. 500 &mgr;g/rat). These results suggest that acute hypoxia produces an intensity- and duration-dependent release of OXT and that such release may be modulated in part by hypoxia-activated high circulating glucocorticoids and their negative feedback on the release of corticotropin releasing hormone (CRH).


Development, validation, and application of an ultra-performance liquid chromatography-sector field inductively coupled plasma mass spectrometry method for simultaneous determination of six organotin compounds in human serum.
Organotin compounds (OTCs) are heavily employed by industry for a wide variety of applications, including the production of plastics and as biocides. Reports of environmental prevalence, differential toxicity between OTCs, and poorly characterized human exposure have fueled the demand for sensitive, selective speciation methods. The objective of this investigation was to develop and validate a rapid, sensitive, and selective analytical method for the simultaneous determination of a suite of organotin compounds, including butyl (mono-, di-, and tri-substituted) and phenyl (mono-, di-, and tri-substituted) species in human serum. The analytical method utilized ultra-performance liquid chromatography (UPLC) coupled with sector field inductively coupled plasma mass spectrometry (SF-ICP-MS). The small (sub-2 µm) particle size of the UPLC column stationary phase and the sensitivity of the SF-ICP-MS enabled separation and sensitive determination of the analyte suite with a runtime of approximately 3 min. Validation activities included demonstration of method linearity over the concentration range of approximately 0.250-13.661 ng mL(-1), depending on the species; intraday precision of less than 21%, interday precision of less than 18%, intraday accuracy of -5.3% to 19%, and interday accuracy of -14% to 15% for all species; specificity, and matrix impact. In addition, sensitivity, and analyte stability under different storage scenarios were evaluated. Analyte stability was found to be limited for most species in freezer, refrigerator, and freeze-thaw conditions. The validated method was then applied for the determination of the OTCs in human serum samples from women participating in the Snart-Foraeldre/MiljØ (Soon-Parents/Environment) Study. The concentration of each OTC ranged from below the experimental limit of quantitation to 10.929 ng tin (Sn) mL(-1) serum. Speciation values were confirmed by a total Sn analysis.


PI3K/AKT, MAPK and AMPK signalling: protein kinases in glucose homeostasis.
New therapeutic approaches to counter the increasing prevalence of obesity and type 2 diabetes mellitus are in high demand. Deregulation of the phosphoinositide-3-kinase (PI3K)/v-akt murine thymoma viral oncogene homologue (AKT), mitogen-activated protein kinase (MAPK) and AMP-activated protein kinase (AMPK) pathways, which are essential for glucose homeostasis, often results in obesity and diabetes. Thus, these pathways should be attractive therapeutic targets. However, with the exception of metformin, which is considered to function mainly by activating AMPK, no treatment for the metabolic syndrome based on targeting protein kinases has yet been developed. By contrast, therapies based on the inhibition of the PI3K/AKT and MAPK pathways are already successful in the treatment of diverse cancer types and inflammatory diseases. This contradiction prompted us to review the signal transduction mechanisms of PI3K/AKT, MAPK and AMPK and their roles in glucose homeostasis, and we also discuss current clinical implications.


The enantioselective construction of chiral spirooxindole-based 4-thiazolidinone via asymmetric catalytic formal [3+2] annulation using a bifunctional catalyst.
4-Thiazolidinone is regarded as a privileged structural unit in bioactive compounds. However, there is still no example of a catalytic method for the synthesis of chiral 4-thiazolidinone until now. We reported herein a facile and efficient method for the construction of chiral spirooxindole-based 4-thiazolidinone. This methodology is based on the asymmetric formal [3+2] annulation of 1,4-dithiane-2,5-diol to ketimines which is followed by simple oxidation, featuring a broad substrate scope with high enantioselectivity (up to 98% ee). The method has been successfully applied to the synthesis of a novel class of mycobacterium tuberculosis inhibitor-spirooxindole based 4-thiazolidinone.


Expression of the ABC transport proteins MDR1 (ABCB1) and BCRP (ABCG2) in bovine rumen.
Rumen fermentation of plant-based forage in bovines is the major site for generation and absorption of short-chain fatty acids. Consequentially, the rumen is also the site for initial exposure to toxins released from diet. Accordingly, we have investigated the expression of bovine ABC transporters in the rumen associated with cytoprotection against xenobiotic exposure, namely MDR1 (ABCB1), MRP2 (ABCC2) and BCRP (ABCG2). Bovine rumen samples from the ventral sac were obtained post-mortem from a commercial slaughterhouse after humane killing. Rumen papilla samples were then prepared for total RNA isolation for RT-PCR, SDS-PAGE/Western blotting and immunohistochemistry. PCR products of the predicted size were observed for both MDR1 and BCRP, but not for MRP2 using bovine-specific primers. β-actin was used as a control transcript. Western blot analysis using C219 primary monoclonal antibody revealed MDR1 protein expression in bovine rumen (Mapp, of ~170-180 kD). Immunolocalisation of MDR1 using UIC2 monoclonal antibody within cryosections of bovine rumen showed extensive membrane staining in the cells of the stratum granulosum, stratum spinosum and stratum basale. MDR1 expression was absent from outer stratum corneum. Protein expression and immunolocalisation were also confirmed for BCRP, with prevalent staining in the stratum basale, becoming weaker in the stratum spinosum and stratum granulosum.


Osteoconduction and osteoinduction of low-temperature 3D printed bioceramic implants.
Rapid prototyping is a valuable implant production tool that enables the investigation of individual geometric parameters, such as shape, porosity, pore size and permeability, on the biological performance of synthetic bone graft substitutes. In the present study, we have employed low-temperature direct 3D printing to produce brushite and monetite implants with different geometries. Blocks predominantly consisting of brushite with channels either open or closed to the exterior were implanted on the decorticated lumbar transverse processes of goats for 12 weeks. In addition, similar blocks with closed channel geometry, consisting of either brushite or monetite were implanted intramuscularly. The design of the channels allowed investigation of the effect of macropore geometry (open and closed pores) and osteoinduction on bone formation orthotopically. Intramuscular implantation resulted in bone formation within the channels of both monetite and brushite, indicating osteoinductivity of these resorbable materials. Inside the blocks mounted on the transverse processes, initial channel shape did not seem to significantly influence the final amount of formed bone and osteoinduction was suggested to contribute to bone formation.


Extracellular Vesicles Derived from Neural Progenitor Cells--a Preclinical Evaluation for Stroke Treatment in Mice.
Stem cells such as mesenchymal stem cells (MSCs) enhance neurological recovery in preclinical stroke models by secreting extracellular vesicles (EVs). Since previous reports have focused on the application of MSC-EVs only, the role of the most suitable host cell for EV enrichment and preclinical stroke treatment remains elusive. The present study aimed to evaluate the therapeutic potential of EVs derived from neural progenitor cells (NPCs) following experimental stroke. Using the PEG technique, EVs were enriched and characterized by electron microscopy, proteomics, rt-PCR, nanosight tracking analysis, and Western blotting. Different dosages of NPC-EVs displaying a characteristic profile in size, shape, cargo protein, and non-coding RNA contents were incubated in the presence of cerebral organoids exposed to oxygen-glucose deprivation (OGD), significantly reducing cell injury when compared with control organoids. Systemic administration of NPC-EVs in male C57BL6 mice following experimental ischemia enhanced neurological recovery and neuroregeneration for as long as 3 months. Interestingly, the therapeutic impact of such NPC-EVs was found to be not inferior to MSC-EVs. Flow cytometric analyses of blood and brain samples 7 days post-stroke demonstrated increased blood concentrations of B and T lymphocytes after NPC-EV delivery, without affecting cerebral cell counts. Likewise, a biodistribution analysis after systemic delivery of NPC-EVs revealed the majority of NPC-EVs to be found in extracranial organs such as the liver and the lung. This proof-of-concept study supports the idea of EVs being a general concept of stem cell-induced neuroprotection under stroke conditions, where EVs contribute to reverting the peripheral post-stroke immunosuppression.


Differential effects of halothane and isoflurane on carotid body glomus cell intracellular Ca2+ and background K+ channel responses to hypoxia.
We recently reported that volatile anaesthetics directly depress the isolated glomus cell response to hypoxia, halothane more so than sevoflurane, in a manner mimicking the action of these agents on the human hypoxic ventilatory response. We wished to extend these investigations to action of another agent (isoflurane), and we planned to examine the effects of this agent and halothane on background K(+) channels. In an isolated rat pup glomus cell preparation intracellular calcium [Ca(2+)]i (measured using indo-1 dye), halothane and isoflurane (0.45-2.73 MAC) depressed the Ca(2+) transient response to hypoxia (p = 0.028), halothane more than isoflurane (p < 0.001). Evaluating the effects of halothane, isoflurane (both 2.5 MAC) and hypoxia on the open probability of background TASK-like K(+) channels in cell attached patch recordings, halothane in euoxia strongly increased channel activity (2 fold) but isoflurane only increased activity by 50% (p < 0.001). In the presence of hypoxia halothane also increased channel activity (3 fold) while isoflurane again only had weak effects (p = 0.004). Thus there were marked differences between these agents on K(+) channel activity, comparable to their effects on the hypoxia induced Ca(2+) transient. When glomus cells were exposed to a depolarising stimulus using 100 mM K(+), both halothane and isoflurane modestly reduced the magnitude of the resulting Ca(2+) transient (by 44% and 10% respectively, p < 0.001). We conclude that the effect of volatile anaesthetics on the glomus cell response to hypoxia is mediated at least in part by their effect on background K(+) channels, and that this plausibly explains their whole-body effect. An additional effect on voltage-gated Ca(2+) is also possible.


Functional significance of the specific sites phosphorylated in desmin at cleavage furrow: Aurora-B may phosphorylate and regulate type III intermediate filaments during cytokinesis coordinatedly with Rho-kinase.
Aurora-B is a protein kinase required for chromosome segregation and the progression of cytokinesis during the cell cycle. We report here that Aurora-B phosphorylates GFAP and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. The sites phosphorylated by Aurora-B; Thr-7/Ser-13/Ser-38 of GFAP, and Thr-16 of desmin are common with those related to Rho-associated kinase (Rho-kinase), which has been reported to phosphorylate GFAP and desmin at cleavage furrow during cytokinesis. We identified Ser-59 of desmin to be a specific site phosphorylated by Aurora-B in vitro. Use of an antibody that specifically recognized desmin phosphorylated at Ser-59 led to the finding that the site is also phosphorylated specifically at the cleavage furrow during cytokinesis in Saos-2 cells. Desmin mutants, in which in vitro phosphorylation sites by Aurora-B and/or Rho-kinase are changed to Ala or Gly, cause dramatic defects in filament separation between daughter cells in cytokinesis. The results presented here suggest the possibility that Aurora-B may regulate cleavage furrow-specific phosphorylation and segregation of type III IFs coordinatedly with Rho-kinase during cytokinesis.


Contrasting influences of age and sex on muscle fatigue.
Greater resistance to muscle fatigue has been observed in women versus men and in older versus young individuals. As suggested mechanisms for these differences include task intensity and duty cycle, the purpose of this study was to evaluate fatigue in healthy young and older men and women during maximum-effort isometric contractions with a 70% duty cycle (7 s of contraction, 3 s of rest). We hypothesized that no differences in fatigue would be observed across age or sex, in contrast to studies incorporating lower duty cycles. The protocol was carried out on ankle dorsiflexors of older (73 +/- 1 yr) and younger (25 +/- 1 yr) men and women. Volitional and stimulated force, compound muscle action potential, and muscle contractile responses were collected before, during, and immediately after the fatigue protocol. These measurements allowed for assessment of fatigue as well as central and peripheral activation. At baseline, older subjects had longer force half-relaxation times and less twitch potentiation than younger subjects, consistent with a slower muscle phenotype. During contractions, younger subjects fatigued more than older subjects did, with no differences between men and women. Central activation decreased similarly in all groups with fatigue. There were no fatigue-related differences in peripheral excitation or contractile properties attributable to age or sex. These data indicate that age-related differences in fatigue are observed even during intermittent MVC with a high duty cycle, and that these differences are independent of central and peripheral activation. Further, it seems that sex-based differences in both fatigue and central activation failure were abolished with this duty cycle. Overall, these results suggest that age- and sex-based differences in fatigue arise from distinct mechanisms.


Influence of gravity on a granular Maxwell's demon experiment.
In the usual description of the granular Maxwell's demon experiment, where phase separation occurs due to an instability in the densities, the control parameter scales linearly with gravity. In this paper we investigate this scaling experimentally using the properties of diamagnetic particles in strong magnetic-field gradients to reduce and even balance gravitation. We find that phase separation occurs even at vanishingly small gravitational accelerations as is predicted by other theories. This is due to the fact that granular samples tend to form clusters as a result of the inelasticity of the particle collisions. Combining the heat balance of the driven granular gas with the cooling rate and thus the appearance of clustering, we are able to describe the crossover between the limiting cases.


Characteristics of surround inhibition in cat area 17.
The effects of stimuli falling outside the 'classical receptive field' and their influence on the orientation selectivity of cells in the cat primary visual cortex are still matters of debate. Here we examine the variety of effects of such peripheral stimuli on responses to stimuli limited to the receptive field. We first determined the extent of the classical receptive field by increasing the diameter of a circular patch of drifting grating until the response saturated or reached a maximum, and by decreasing the diameter of a circular mask in the middle of an extended grating, centred on the receptive field, until the cell just began to respond. These two estimates always agreed closely. We then presented an optimum grating of medium-to-high contrast filling the classical receptive field while stimulating the surround with a drifting grating that had the same parameters as the central stimulus but was varied in orientation. For all but five neurons (of 37 tested), surround stimulation produced clear suppression over some range of orientations, while none showed explicit facilitation under these conditions. For 11 cells (34% of those showing suppression), the magnitude of suppression did not vary consistently with the orientation of the surround stimulus. In the majority of cells, suppression was weakest for a surround grating oriented orthogonal to the cell's optimum. Nine of these cells (28%) exhibited maximum inhibition at the optimum orientation for the receptive field itself, but for 12 cells (38%) there was apparent 'release' from inhibition for surround gratings at or near the cell's optimum orientation and direction, leaving inhibition either maximal at angles flanking the optimum (9 cells) or broadly distributed over the rest of the orientation range (3 cells). This implies the existence of a subliminal facilitatory mechanism, tightly tuned at or near the cell's optimum orientation, extending outside the classical receptive field. For just two cells of 13 tested the preferred orientation for a central grating was clearly shifted towards the orientation of a surrounding grating tilted away from the cell's optimum. The contrast gain for central stimulation at the optimal orientation was measured with and without a surround pattern. For nine of 25 cells tested, surround stimulation at the cell's optimum orientation facilitated the response to a central grating of low contrast (< or =0.1) but inhibited that to a higher-contrast central stimulus: the contrast-response gain is reduced but the threshold contrast is actually decreased by surround stimulation. Hence the receptive field is effectively larger for low-contrast than for high-contrast stimuli. Inhibition from the periphery is usually greatest at or around the cell's optimum, while suppression within the receptive field has been shown to be largely non-selective for orientation. Inhibition by orientations flanking the optimum could serve to sharpen orientation selectivity in the presence of contextual stimuli and to enhance orientational contrast; and it may play a part in orientation contrast illusions.


The impact of a school-based safe water and hygiene programme on knowledge and practices of students and their parents: Nyanza Province, western Kenya, 2006.
Safe drinking water and hygiene are essential to reducing Kenya's diarrhoeal disease burden. A school-based safe water and hygiene intervention in Kenya was evaluated to assess its impact on students' knowledge and parents' adoption of safe water and hygiene practices. We surveyed 390 students from nine schools and their parents at baseline and conducted a final evaluation of 363 students and their parents. From baseline to final evaluation, improvement was seen in students' knowledge of correct water treatment procedure (21-65%, P<0.01) and knowing when to wash their hands. At final evaluation, 14% of parents reported currently treating their water, compared with 6% at baseline (P<0.01). From 2004 to 2005, school absenteeism in the September-November term decreased in nine project schools by 35% and increased in nine neighbouring comparison schools by 5%. This novel programme shows promise for reducing school absenteeism and promoting water and hygiene interventions in the home.


NineTeen Complex-subunit Salsa is required for efficient splicing of a subset of introns and dorsal-ventral patterning.
The NineTeen Complex (NTC), also known as pre-mRNA-processing factor 19 (Prp19) complex, regulates distinct spliceosome conformational changes necessary for splicing. During Drosophila midblastula transition, splicing is particularly sensitive to mutations in NTC-subunit Fandango, which suggests differential requirements of NTC during development. We show that NTC-subunit Salsa, the Drosophila ortholog of human RNA helicase Aquarius, is rate-limiting for splicing of a subset of small first introns during oogenesis, including the first intron of gurken Germline depletion of Salsa and splice site mutations within gurken first intron impair both adult female fertility and oocyte dorsal-ventral patterning, due to an abnormal expression of Gurken. Supporting causality, the fertility and dorsal-ventral patterning defects observed after Salsa depletion could be suppressed by the expression of a gurken construct without its first intron. Altogether, our results suggest that one of the key rate-limiting functions of Salsa during oogenesis is to ensure the correct expression and efficient splicing of the first intron of gurken mRNA. Retention of gurken first intron compromises the function of this gene most likely because it undermines the correct structure and function of the transcript 5'UTR.


Discharge Against Medical Advice in Traumatic Brain Injury: Follow-Up and Readmission Rate.
Patients who leave hospital against medical advice (AMA) may be at risk of adverse health outcomes, medical complications, and readmission. In this study, we examined the characteristics of patients who left AMA after traumatic brain injury (TBI), their rates of follow-up visits, and readmission. We retrospectively studied 106 consecutive patients who left the tertiary trauma center AMA (1.8% of all admitted patients with a TBI). Preinjury health and social issues, mechanism of injury, computed tomography findings, and injury markers were collected. They were correlated to compliance with follow-up visits and unplanned emergency room (ER) visits and readmission rates. The most prevalent premorbid health or social-related issues were alcohol abuse (33%) and assault as a mechanism of trauma (33%). Only 15 (14.2%) subjects came to follow-up visit for their TBI. Sixteen (15.1%) of the 106 subjects had multiple readmissions and/or ER visits related to substance abuse. Seven (6.6%) had multiple readmissions or ER visits with psychiatric reasons. Those patients with multiple readmissions and ER visits showed in higher proportion preexisting neurological condition (p=0.027), homelessness (p=0.012), previous neurosurgery (p=0.014), preexisting encephalomalacia (p=0.011), and had a higher ISS score (p=0.014) than those who were not readmitted multiple times. The significantly increased risks of multiple follow-up visits and readmission among TBI patients who leave hospital AMA are related to a premorbid vulnerability and psychosocial issues. Clinicians should target AMA TBI patients with premorbid vulnerability for discharge transition interventions.


Quantitative measurement of endogenous estrogens and estrogen metabolites in human serum by liquid chromatography-tandem mass spectrometry.
Endogenous estrogen plays a key role in the development of human breast cancer, yet the contribution of specific estrogen metabolites and patterns of estrogen metabolism remains unclear. To determine their individual and joint roles in breast carcinogenesis, it is necessary to be able to measure quantitatively each estrogen metabolite in epidemiologic and clinical biospecimens. In this report, we detail a sensitive, specific, accurate, and precise high-performance liquid chromatography-tandem mass spectrometry method utilizing selected reaction monitoring for measuring the absolute quantities of free (unconjugated) and total (conjugated + unconjugated) endogenous estrogens and estrogen metabolites in human serum from premenopausal and postmenopausal women. The method requires a simple sample preparation and only 0.5 mL of serum, yet is capable of quantifying simultaneously 15 estrogens and estrogen metabolites (EM): estrone and its 2-, 4-, and 16alpha-hydroxy and 2- and 4-methoxy derivatives; 2-hydroxyestrone-3-methyl ether; 17beta-estradiol and its 2-hydroxy and 2- and 4-methoxy derivatives; and estriol, 17-epiestriol, 16-ketoestradiol, and 16-epiestriol. The lower limit of quantitation for each EM was 0.4 pg on-column, equivalent to 8 pg/mL (26.5-29.6 fmol/mL) in the original serum sample. Calibration curves were linear over a 10(3)-fold concentration range. For a stripped serum sample containing 8 pg/mL of each EM, accuracy (percent recovery of a known added amount) ranged from 91 to 113%. Intrabatch precision (including hydrolysis, extraction, and derivatization steps) ranged from 7 to 30% relative standard deviation (RSD), and interbatch precision ranged from 8 to 29% RSD. Since distinct roles have been proposed for many of these estrogen metabolites, an accurate, precise, sensitive, and specific method for measuring their levels in circulation should suggest new approaches to breast cancer prevention, screening, and treatment.


An update of evaluation of intravenous sedation on diagnostic spinal injection procedures.
Intravenous (IV) sedation analgesia is often employed in patients with chronic spinal pain undergoing diagnostic spinal injection procedures. The drugs used for intravenous sedation analgesia produce varying degrees of sedation, amnesia, anxiolysis, muscle relaxation, and analgesia. The very nature of these pharmacologic effects in altering the patient's level of consciousness, awareness, or response to a particular diagnostic stimulus invokes a sense of uncertainty about the results or response obtained from the diagnostic procedure. There is an ongoing controversy regarding the validity of controlled diagnostic blocks due to variability in sensitivity, specificity, and accuracy. Moreover, there is no consensus with regards to the use of sedation analgesic measures prior to controlled diagnostic blocks and their influence on the accuracy and validity of a diagnosis. To assess and update the clinically significant effects sedation analgesia procedures have on the diagnostic accuracy and validity of interventional spinal techniques. A comprehensive literature search using PubMed, EMBASE, and Cochrane Library review databases up to September 2012 was performed. The search included systematic and narrative review articles, prospective and retrospective studies, as well as cross-referencing of bibliographies from notable primary and review articles and abstracts from scientific meetings and peer-reviewed non-indexed journals. The search emphasized the effects of sedation analgesia on diagnostic spinal interventions. Based on a review of the available evidence, it appears that the administration of mild to moderate sedation does not confound the results or diagnostic validity of spinal injection procedures. Specifically, immediate pain relief after cervical and lumbar facet joint controlled nerve blocks is not enhanced by IV sedation with midazolam or fentanyl. This is especially true if stringent outcome criteria are employed, such as at least 75% pain relief combined with an increase in range of motion for pain limited movements.


Clonal analysis of immunoglobulin mRNA in rheumatoid arthritis synovium: characterization of expanded IgG3 populations.
Plasma cells secreting IgG, M, and A abound in the synovium of patients with rheumatoid arthritis, yet their immunoglobulin repertoire and clonal relationship remain to be elucidated. Locally synthesized immunoglobulins probably contribute to the chronic joint inflammatory processes which are characteristic of these patients. To determine whether B lymphocyte proliferation contributes to the synovial plasma cell infiltrate, the clonality of IgG mRNA in individual synovial biopsies from an actively inflamed joint of patients with rheumatoid arthritis was investigated by a combination of cDNA length analysis and DNA sequencing. Particular sizes of immunoglobulin cDNA, detectable in subclasses 1, 3, or 4, were expressed in most synovial biopsies from one patient, suggesting their origin from expanded clones present in each biopsy. To prove a clonal relationship between recurrent cDNA lengths, immunoglobulin cDNA was cloned from three regions of synovium in three patients. The sequence of clones with a recurrent cDNA length was determined. An IgG3 clone found in most synovial biopsies of one patient was encoded by an unmutated copy of the V(H)1 gene, DP7. In contrast, IgG3 clones encoded by mutated versions of the V(H)3 gene DP49 or the V(H)4 gene DP63 were expanded in the other two patients. Different somatic mutants of these clones were isolated from different sites in these patients. The ratio of replacement/silent somatic mutations in these two families of clones suggests that the selective clonal expansion in the synovium of patients with rheumatoid arthritis is due to an antigen-driven immune response.


Multimodality Imaging Findings in Carcinoid Tumors: A Head-to-Toe Spectrum.
Carcinoid tumors are a rare biologically heterogeneous group of neuroendocrine tumors with a spectrum ranging from benign indolent to aggressive metastatic tumors. They belong to the category of amine precursor uptake and decarboxylase tumors, or apudomas. The most common sites for primary locations are the gastrointestinal and respiratory tracts; however, any organ can be involved. The clinical presentation depends on location, aggressiveness, production of biologically active amines and peptides, paraneoplastic syndromes, and tendency for metastasis. Their reported age-adjusted incidence has increased in recent years, partly due to improved detection at radiologic imaging and endoscopy. Not a ll neuroendocrine cell tumors are carcinoids. Numerous systems have been proposed regarding their nomenclature and classification. Cross-sectional and functional imaging plays an important role in diagnosis, lesion characterization, and staging. Awareness of nomenclature, classification, common sites of involvement, and imaging presentation are pivotal for making the diagnosis. Knowledge of the diverse clinical, pathologic, and radiologic spectrum of carcinoid tumors involving various organs of the body is important for diagnosis and patient management. ©RSNA, 2017.


Peak-shifting in real-time time-dependent density functional theory.
In recent years, the development and application of real-time time-dependent density functional theory (RT-TDDFT) has gained momentum as a computationally efficient method for modeling electron dynamics and properties that require going beyond a linear response of the electron density. However, the RT-TDDFT method within the adiabatic approximation can unphysically shift absorption peaks throughout the electron dynamics. Here, we investigate the origin of these time-dependent resonances observed in RT-TDDFT spectra. Using both exact exchange and hybrid exchange-correlation approximate functionals, adiabatic RT-TDDFT gives time-dependent absorption spectra in which the peaks shift in energy as populations of the excited states fluctuate, while exact wave function methods yield peaks that are constant in energy but vary in intensity. The magnitude of the RT-TDDFT peak shift depends on the frequency and intensity of the applied field, in line with previous studies, but it oscillates as a function of time-dependent molecular orbital populations, consistent with a time-dependent superposition electron density. For the first time, we provide a rationale for the direction and magnitude of the time-dependent peak shifts based on the molecular electronic structure. For three small molecules, H2, HeH(+), and LiH, we give contrasting examples of peak-shifting to both higher and lower energies. The shifting is explained as coupled one-electron transitions to a higher and a lower lying state. Whether the peak shifts to higher or lower energies depends on the relative energetics of these one-electron transitions.


Insights from mathematical modelling and quantitative analysis on the proposed 2030 goals for trachoma.
Trachoma is a neglected tropical disease and the leading infectious cause of blindness worldwide. The current World Health Organization goal for trachoma is elimination as a public health problem, defined as reaching a prevalence of trachomatous inflammation-follicular below 5% in children (1-9 years) and a prevalence of trachomatous trichiasis in adults below 0.2%. Current targets to achieve elimination were set to 2020 but are being extended to 2030. Mathematical and statistical models suggest that 2030 is a realistic timeline for elimination as a public health problem in most trachoma endemic areas. Although the goal can be achieved, it is important to develop appropriate monitoring tools for surveillance after having achieved the elimination target to check for the possibility of resurgence. For this purpose, a standardized serological approach or the use of multiple diagnostics in complement would likely be required.


Effect of n-3 long chain polyunsaturated fatty acid supplementation in pregnancy on infants' allergies in first year of life: randomised controlled trial.
To determine whether dietary n-3 long chain polyunsaturated fatty acid (LCPUFA) supplementation of pregnant women with a fetus at high risk of allergic disease reduces immunoglobulin E associated eczema or food allergy at 1 year of age. Follow-up of infants at high hereditary risk of allergic disease in the Docosahexaenoic Acid to Optimise Mother Infant Outcome (DOMInO) randomised controlled trial. Adelaide, South Australia. 706 infants at high hereditary risk of developing allergic disease whose mothers were participating in the DOMInO trial. The intervention group (n=368) was randomly allocated to receive fish oil capsules (providing 900 mg of n-3 LCPUFA daily) from 21 weeks' gestation until birth; the control group (n=338) received matched vegetable oil capsules without n-3 LCPUFA. Immunoglobulin E associated allergic disease (eczema or food allergy with sensitisation) at 1 year of age. No differences were seen in the overall percentage of infants with immunoglobulin E associated allergic disease between the n-3 LCPUFA and control groups (32/368 (9%) v 43/338 (13%); unadjusted relative risk 0.68, 95% confidence interval 0.43 to 1.05, P=0.08; adjusted relative risk 0.70, 0.45 to 1.09, P=0.12), although the percentage of infants diagnosed as having atopic eczema (that is, eczema with associated sensitisation) was lower in the n-3 LCPUFA group (26/368 (7%) v 39/338 (12%); unadjusted relative risk 0.61, 0.38 to 0.98, P=0.04; adjusted relative risk 0.64, 0.40 to 1.02, P=0.06). Fewer infants were sensitised to egg in the n-3 LCPUFA group (34/368 (9%) v 52/338 (15%); unadjusted relative risk 0.61, 0.40 to 0.91, P=0.02; adjusted relative risk 0.62, 0.41 to 0.93, P=0.02), but no difference between groups in immunoglobulin E associated food allergy was seen. n-3 LCPUFA supplementation in pregnancy did not reduce the overall incidence of immunoglobulin E associated allergies in the first year of life, although atopic eczema and egg sensitisation were lower. Longer term follow-up is needed to determine if supplementation has an effect on respiratory allergic diseases and aeroallergen sensitisation in childhood. Australian New Zealand Clinical Trials Registry ACTRN12610000735055 (DOMInO trial: ACTRN12605000569606).


Comparison of UK and US methods for weighting and scoring the SF-36 summary measures.
The SF-36 is a widely used measure of health status that can be scored to provide either a profile of eight scores or two summary measures of health, the Physical Component Summary and Mental Component Summary (PCS and MCS). Scoring of the summary scales is undertaken by weighting and summing the original eight dimensions. These weights are gained from factor analysis of data from a general population and have been assumed to be country specific. However, it has been suggested that the weights gained from the US developers could be applied to all datasets, throughout the world, for purposes of comparability and simplicity. The purpose of this study is to evaluate US and UK scoring schemes in a UK population dataset, and in a cohort study of elderly congestive heart failure patients receiving standard therapy and a trial of open vs laparoscopic surgery for hernia repair. This paper compares algorithms developed in the USA and the UK for the calculation of the Physical and Mental Health Summary scores (PCS and MCS) for the SF-36 health status measure. In this study the PCS and MCS were calculated using a weighting scheme recommended by the developers and derived from a US population sample dataset, as well as being calculated from weights derived from an UK population sample dataset. The two methods produced similar results, both cross-sectionally and in the assessment of change. It is suggested that it may be necessary to weight the PCS and MCS using only the original US algorithms, which will lead to more uniform analysis of datasets and may also lead to greater uptake of the summary measures. Furthermore, the results would suggest that in international trials the SF-36 can be adopted and summary scores calculated for countries where no large-scale normative dataset is available. However, further research is needed to determine that the similarity of results gained using UK and US algorithms is not an idiosyncratic feature of the UK data. Studies to verify the findings reported here are required from other countries.


Nerve agent hydrolysis activity designed into a human drug metabolism enzyme.
Organophosphorus (OP) nerve agents are potent suicide inhibitors of the essential neurotransmitter-regulating enzyme acetylcholinesterase. Due to their acute toxicity, there is significant interest in developing effective countermeasures to OP poisoning. Here we impart nerve agent hydrolysis activity into the human drug metabolism enzyme carboxylesterase 1. Using crystal structures of the target enzyme in complex with nerve agent as a guide, a pair of histidine and glutamic acid residues were designed proximal to the enzyme's native catalytic triad. The resultant variant protein demonstrated significantly increased rates of reactivation following exposure to sarin, soman, and cyclosarin. Importantly, the addition of these residues did not alter the high affinity binding of nerve agents to this protein. Thus, using two amino acid substitutions, a novel enzyme was created that efficiently converted a group of hemisubstrates, compounds that can start but not complete a reaction cycle, into bona fide substrates. Such approaches may lead to novel countermeasures for nerve agent poisoning.