Management of oxygen and carbon dioxide pressure after cardiac arrest.
Experimental evidence shows that derangements of arterial partial pressures of either oxygen (PaO2) and carbon dioxide (PaCO2) immediately after resuscitation from cardiac arrest may increase the severity of organ dysfunction due to whole body ischemia and subsequent reperfusion. Hyperoxia is believed to increase reperfusion injury, especially to mitochondrial membrane due to increased production of reactive oxygen species. Two large observational studies in human adults showed that hyperoxia (defined as a PaO2≥300 mmHg) in the first 24 h after hospital admission was associated with increased mortality or lower likelihood of independent functional status at hospital discharge. Evidence of the effects of hyperoxia in children were less consistent. A reduction of PaCO2 below normal values may cause cerebral vasoconstriction and increase the severity of delayed brain hypopefusion which usually occurs within 24h from resuscitation. Cerebrovascular reactivity to CO2 is preserved during therapeutic hypothermia. According to recent clinical studies, a low PaCO2 after resuscitation is associated with increased mortality and higher rates of poor neurological outcome both in children and in adults, while the effects of a PaCO2 above 45 mmHg are less clear. The PaCO2 derangements are very common in resuscitated patients. Maintaining normal levels of both PaO2 and PaCO2 and in particular avoiding both hyperoxia and hypocapnia may reduce morbidity and improve survival of cardiac arrest survivors. Available clinical evidence is however almost exclusively limited to observational studies which may be biased by potential uncontrolled confounders.


Irreversible dual inhibitory mode: the novel Btk inhibitor PLS-123 demonstrates promising anti-tumor activity in human B-cell lymphoma.
The B-cell receptor (BCR) signaling pathway has gained significant attention as a therapeutic target in B-cell malignancies. Recently, several drugs that target the BCR signaling pathway, especially the Btk inhibitor ibrutinib, have demonstrated notable therapeutic effects in relapsed/refractory patients, which indicates that pharmacological inhibition of BCR pathway holds promise in B-cell lymphoma treatment. Here we present a novel covalent irreversible Btk inhibitor PLS-123 with more potent anti-proliferative activity compared with ibrutinib in multiple cellular and in vivo models through effective apoptosis induction and dual-action inhibitory mode of Btk activation. The phosphorylation of BCR downstream activating AKT/mTOR and MAPK signal pathways was also more significantly reduced after treatment with PLS-123 than ibrutinib. Gene expression profile analysis further suggested that the different selectivity profile of PLS-123 led to significant downregulation of oncogenic gene PTPN11 expression, which might also offer new opportunities beyond what ibrutinib has achieved. In addition, PLS-123 dose-dependently attenuated BCR- and chemokine-mediated lymphoma cell adhesion and migration. Taken together, Btk inhibitor PLS-123 suggested a new direction to pharmacologically modulate Btk function and develop novel therapeutic drug for B-cell lymphoma treatment.


A new biodegradable nanocomposite based on polyhedral oligomeric silsesquioxane nanocages: cytocompatibility and investigation into electrohydrodynamic jet fabrication techniques for tissue-engineered scaffolds.
Our group has developed a non-biodegradable nanocomposite based on POSS (polyhedral oligomeric silsesquioxane) nanocages with PCU [poly(carbonate urethane)] and previous studies have shown good cell-compatibility and antithrombogenic properties. The latest biodegradable formulation is a POSS-modified poly(hexanolactone/carbonate)urethane/urea containing 80% hexanolactone (caprolactone) with the tradename UCL-NanoBio. The direct effect of the polymer on cells was investigated by seeding stem cells on to circular discs of the polymer in 24-well plates; these discs were prepared mainly by electrohydrodynamic jetting. To assess the indirect effect of the polymer, various concentrations of the polymer powder were added to CCM (cell culture medium) and left on a shaker for 10 days. The precipitate was then removed and the CCM was used for culturing the cells seeded on to 24-well plates. Cell viability and growth at 48 and 96 h were assessed using Alamar Blue and lactate dehydrogenase, and morphology was studied by scanning electron microscopy. Cells were shown to adhere well to the polymer, with cell metabolism being comparable with that found on TCP (tissue-culture plastic). Indirect assessment demonstrated some decrease in cell viability with high concentrations of polymer, but showed no difference in cell death between polymer concentrations. The viability of cells seeded on to the polymer was comparable with that of those seeded on to TCP. Cell viability was comparable on both electrosprayed and electrospun scaffolds, but infiltration into the scaffold was much more evident on the electrospun scaffolds. It can be concluded that this new nanocomposite can support the growth and viability of stem cells and that scaffolds of this polymer nanocomposite fabricated by electrohydrodynamic jetting routes have potential use for tissue engineering in the future.


Effects of polysaccharides from rhizomes of Curcuma zedoaria on macrophage functions.
The effects of Curcuma zedoaria, which is used as a condiment, in perfumery, and as a medicine, on immune response were investigated by measuring macrophage-stimulating activity in macrophages and RAW 264.7 cells. In this study, CZ-1 and CZ-1-III, the fractions partially purified from C. zedoaria, had a strong, dose-dependent lysosomal enzyme activity. It was suggested that active portions of CZ-1-III were polysaccharides rather than proteins. Phagocytic activity increased as a similar pattern in both the gram-negative and gram-positive bacteria, time-dependently. It was demonstrated that CZ-1-III can augment the oxygen burst response but had an even higher activity in vivo than in vitro. Also a significant increase of H2O2, NO, and TNF-alpha production was observed. However, the production of TNF-alpha at the concentration of 1,000 microg/ml decreased. These data suggested that C. zedoaria had macrophage-stimulating activity and the possibility of being used as a biological response modifier.


Nanowire Sensors in Cancer.
In 2006, the group of Dr C.M. Lieber pioneered the field of nanowire sensors by fabricating devices for the ultra-sensitive label-free detection of biological macromolecules. Since then, nanowire sensors have demonstrated their ability to detect cancer-associated analytes in peripheral blood, tumor tissue, and the exhaled breath of cancer patients. These innovative developments have marked a new era with unprecedented detection performance, capable of addressing crucial needs such as cancer diagnosis and monitoring disease progression and patient response to therapy. The ability of nanowire sensors to identify molecular features of patient tumor represents a first step toward precision medicine, and their integration into portable devices has the potential to revolutionize cancer diagnosis and patient monitoring.


Exposure to cigarette promotions and smoking uptake in adolescents: evidence of a dose-response relation.
To assess whether a dose-response relation exists between the number of cigarette promotional items (CPIs) owned by an adolescent, and smoking behaviour. Voluntary, self administered survey of 1265 sixth through to 12th grade students (ages 10-19 years), representing 79-95% of all students attending five rural New Hampshire and Vermont public (state funded) schools in October 1996. The association between the number of CPIs owned by students and smoking behaviour was examined using multivariate regression methods. Adjusted odds of being a smoker (>/= 100 cigarettes lifetime) and, among never and experimental smokers, adjusted cumulative odds of having higher levels on a smoking uptake index given the number of CPIs owned. One third of students owned a CPI (n = 406). Among owners, 211 owned one, 82 owned two, 57 owned three, 24 owned four, 23 owned five, and 7 students owned six CPIs. The number of CPIs owned by students was not associated with grade in school but was significantly higher in males, those with poorer school performance, those who perceived high prevalence of peer smoking, and those with higher exposure to peer and family smoking. The more items a student owned, the greater the chances of being a smoker. For example, smoking prevalence was 11.2% for those not owning a CPI, 41.5% for those owning two, 58.5% for those owning four, and 71.4% for those owning six CPIs. The dose-response relation remained after controlling for confounding; compared with those who did not own a CPI, the likelihood of being a smoker was significantly higher for those who owned one CPI, with an adjusted odds ratio (OR) of 2.7 (95% confidence interval (CI) 1.7 to 4.1); OR was 3.4 (95% CI 1.9 to 5.9) for those owning two CPIs, and 8.4 (95% CI 5.0 to 14.2) for those owning three or more CPIs. After excluding smokers, there was a crude dose-response association between CPI ownership and higher rates of experimentation with cigarettes among sixth to ninth graders (ages 11-15 years) only (n = 543). After controlling for confounding influences, the dose-response relation remained, with the likelihood of being higher on the smoking uptake index rising with the number of CPIs owned: one CPI, adjusted cumulative OR 1.7 (95% CI 1.1 to 2.60); two CPIs, OR 2.5 (95% CI 1.2 to 5.1); and three or more CPIs, OR 4.8 (95% CI 1.9 to 12.2). This study offers evidence of a dose-response relation between the number of CPIs owned by adolescents and higher likelihood of experimental and established smoking. The dose-response relation persists after controlling for confounding influences. These data provide further support of a causal relation between tobacco promotional campaigns and smoking behaviour among adolescents.


IgE antibodies and urinary trimethylarsine oxide accounted for 1-7% population attributable risks for eczema in adults: USA NHANES 2005-2006.
Population attributable risks from serum IgE and dust miteallergen concentrations and environmental chemicals for eczema are unclear. Therefore, it was aimed to examine serum IgE and allergen concentrations and environmental chemicals for eczema in adults and to calculate population attributable risks in a national and population-based setting. Data retrieved from the National Health and Nutrition Examination Survey, 2005-2006, was analyzed. Information on demographics and self-reported ever eczema was obtained by household interview. Bloods and urines (sub-sample) were also collected during the interview. Adults aged 20-85 were included. Statistical analyses were using chi-square test, t test, survey-weighted logistic regression modeling, and population attributable risk (PAR) estimation. Of all the included American adults (n = 4979), 310 (6.2%) reported ever eczema. Moreover, more eczema cases were observed in female adults but fewer cases in people born in Mexico. There were no significant associations observed between commonly known biomarkers (including vitamin D) and eczema or between dust mite allergens and eczema. Serum D. Farinae (PAR 1.0%), D. Pteronyssinus (PAR 1.1%), cat (PAR 1.8%), dog (PAR 1.6%), and muse (PAR 3.2%) IgE antibodies were associated with eczema. Adults with ever eczema were found to have higher levels of urinary trimethylarsine oxide concentrations (PAR 7.0%) but not other speciated arsenic concentrations. There were no clear associations between other environmental chemicals including heavy metals, phthalates, phenols, parabens, pesticides, nitrate, perchlorate, polycyclic hydrocarbons and eczema as well. Elimination of environmental risks might help delay or stop eczema up to 7% in the adult population.


Comparison of different measurement methods of odour and odorants used in the odour impact assessment of wastewater treatment plants in Poland.
The aim of this study was to compare sensory and analytical methods used to measure odour and odorants concentrations for odour impact assessment on municipal wastewater treatment plants (WWTPs). A range of sources and odour or odorants concentrations were used to compare the methods. Four different odours and odorants measurement methods were compared: field olfactometry using Nasal Ranger® field olfactometer, dynamic olfactometry according to PN-EN 13725:2007 standard, colorimetric assays (hydrogen sulphide, ammonia) and gas chromatography-mass spectrometry (GC-MS) methods (methanethiol, ethanethiol, dimethyl sulphide). Mechanical-biological and mechanical-biological-chemical WWTPs were chosen. Receptor points were selected inside of 'closed' facilities of the technological line (screening rooms, mechanical thickening and dewatering building) and downwind at 'open' facilities (collection chambers, sand trap, mechanical thickeners) which were the most significant regarding the potential for odour nuisance. By the research, it is not possible to specify explicit dependencies between results obtained from different research methods used in the odour impact assessment of WWTPs. A strong correlation (Pearson's correlation coefficient was equal R = 0.79) was determined only once between odour concentrations measured by dynamic olfactometry and methanethiol concentrations in the screen room at the WWTP No. 3.


Thermostable (SULT1A1) and thermolabile (SULT1A3) phenol sulfotransferases in human osteosarcoma and osteoblast cells.
Sulfate conjugation is an important pathway in the metabolism of many drugs, xenobiotic compounds, and hormones. Sulfotransferases (SULTs) catalyze these reactions and have been detected and characterized in various human tissues including the liver and small intestine. Substrates for SULTs that include estrogen and thyroid hormones have well-established roles affecting skeletal integrity and disease processes. We performed the following studies to determine the presence of SULTs in human osteoblast-like cells, and to compare their characteristics to SULTs expressed in other human tissues. Four osteosarcoma cell lines (SaOS-2, U2-OS, PR, and HOS-TE85) were screened for the presence of four different SULT activities. Predominant activities were found for SULT1A1 in SaOS-2 cells, and SULT-1A3 in HOS-TE85 cells. Several biochemical properties of each enzyme that included apparent K(m) values, thermal stabilities, and responses to the inhibitors 2,6-dichloro-4-nitrophenol and NaCl were used to further characterize the SULT activities. High-performance liquid chromatography (HPLC) of the reaction products confirmed the known products of SULT1A1 and SULT1A3. When the mature human osteoblast HOB-03-CE6 cell line was tested for activity alone, the predominant activity was SULT1A3, with minimal SULT1A1. The results indicate that SULT1A1 and SULT1A3 are present in human osteosarcoma and mature osteoblast cell lines, and that the characteristics of the osteosarcoma cell SULTs are similar to those expressed in other human tissues. SULTs may have regulatory roles in the deactivation of thyroid hormones or estrogenic compounds in bone, and thus may affect hormone action and bone responses in the human skeleton.


Role of motor vehicle lifetime extension in climate change policy.
Vehicle replacement schemes such as the "cash for clunkers" program in the U.S. and the "scrappage scheme" in the UK have featured prominently in the economic stimulation packages initiated by many governments to cope with the global economic crisis. While these schemes were designed as economic instruments to support the vehicle production industry, governments have also claimed that these programs have environmental benefits such as reducing CO2 emissions by bringing more fuel-efficient vehicles onto the roads. However, little evidence is available to support this claim as current energy and environmental accounting models are inadequate for comprehensively capturing the economic and environmental trade-offs associated with changes in product life and product use. We therefore developed a new dynamic model to quantify the carbon emissions due to changes in product life and consumer behavior related to product use. Based on a case study of Japanese vehicle use during the 1990-2000 period, we found that extending, not shortening, the lifetime of a vehicle helps to reduce life-cycle CO2 emissions throughout the supply chain. Empirical results also revealed that even if the fuel economy of less fuel-efficient ordinary passenger vehicles were improved to levels comparable with those of the best available technology, i.e. hybrid passenger cars currently being produced in Japan, total CO2 emissions would decrease by only 0.2%. On the other hand, we also find that extending the lifetime of a vehicle contributed to a moderate increase in emissions of health-relevant air pollutants (NOx, HC, and CO) during the use phase. From the results, this study concludes that the effects of global warming and air pollution can be somewhat moderated and that these problems can be addressed through specific policy instruments directed at increasing the market for hybrid cars as well as extending lifetime of automobiles, which is contrary to the current wisdom.


Size dependent surface reconstruction in detonation nanodiamonds.
Nanometer-sized diamond particles are used in bio-medical applications, where the nature of the nanodiamond surfaces is crucial to achieving correct functionalisation. Herein, using high-resolution transmission electron microscopy and electronic structure calculations, we study the surface reconstructions that occur in detonation-synthesized nanodiamonds. Our results show that particles smaller than 3 nm exhibit size- and shape-dependent surface reconstructions, and that the surfaces can exhibit a higher-than-expected fraction of sp2+x bonding. This indicates an aliphatic character for sub-3 nm nanodiamond particles. Such behaviour impacts the functionality of nanodiamonds, where both size and surface charge can drive performance. Our observations offer a potential strategy for better functionalization control via the size range of the particles.


Heterodimerization between two classes of homeodomain proteins in the mushroom Coprinus cinereus brings together potential DNA-binding and activation domains.
The A mating type-genes of the mushroom, Coprinus cinereus, encode two classes of homeodomain-containing proteins distinguished as HD1 and HD2 on the basis of conserved, but distinctly different motifs. Compatible mating partners bring together versions of the proteins that can heterodimerize, thereby generating an active transcription factor complex that commits mated cells to sexual development. We have previously described a rare mutation in which an HD2::HD1 gene fusion generates a 'fused dimer' lacking much of HD1 including the homeodomain yet capable of constitutively promoting development [Kües et al., EMBO J. 13 (1994b) 4054-4059]. Here, we exploit this mutation to help identify contributions made by each protein class to normal heterodimer function. We show that the HD2 homeodomain is essential; deletion within the HD1 homeodomain can be tolerated in a normal heterodimer, as well as in the mutant fusion protein, but not substitution of a critical amino acid. We define, by deletion analysis, an essential C-terminal region of the HD1 and demonstrate its potential activation function by the ability to activate transcription in yeast when fused to the GAL4 DNA-binding domain. We also identify a potential role in transcriptional repression for the predicted C-terminal helix of HD1 proteins.


Social and structural barriers for adherence to methadone maintenance treatment among Vietnamese opioid dependence patients.
Methadone maintenance treatment (MMT) services may reduce the risk of HIV transmission if patients completely adhere to the treatment. Identifying adherence patterns and potential related factors is vital for the sustainability of MMT program in Vietnam. This study examined social and structural factors associated with adherence to MMT among patients in different service delivery models. A total of 510 patients at three MMT clinics in Hanoi were interviewed. Measures of self-reported adherence included the number of missed doses in the past 7 days and the level of adherence in the past 30 days using a visual analog scale (VAS) scoring from 0 (non-adherence) to 100 (perfect adherence). Multivariate regressions were employed to identify factors associated with non-adherence to MMT. A total of 17.7% of participants reported incomplete MMT adherence in the last 30 days and 8.3% reported missing a dose in the last seven days, respectively. Living with HIV/AIDS, poor self-care and usual activities, and disclosure of health issues to spouses or intimate partners were associated with non-adherence. Those patients with pain or depression were more likely to report better adherence. Disclosing health status to spouse/partner increased the risk of incomplete adherence, while disclosing to friends reduced the number of missed dose in the last seven days. Patients attending clinics with comprehensive services had a lower VAS score of adherence compared to those enrolling in clinics with only MMT and general health care. Sustaining the compliance of patients to MMT is principal in the rapid expansion of this service in Vietnam. It is necessary to address the complexity of health care demands of drug users, their difficulties to be rehabilitated into workforce and society, and the stigmatization to maximize the outcomes of MMT program.


Quality control in upper gastrointestinal endoscopy: detection rates of gastric cancer in Oxford 2005-2008.
Gastric cancer (GC) represents the sum of advanced gastric cancer (AGC) and early gastric cancer (EGC). Endoscopy (with biopsies) is the gold standard for detection of GC, but a false-negative rate of up to 19% is reported. To determine whether patients with GC had had an oesophagogastroduodenoscopy (OGD) in the year preceding diagnosis that might reasonably have been expected to detect the cancer, as a measure of quality assurance of endoscopic practice. Patients with histologically proven GC were identified from pathology records. Endoscopy reports and case notes were examined to identify any OGD before diagnosis, the interval and endoscopic findings. A false-negative OGD was defined as one where GC was neither suspected nor shown at pathology, but where a diagnosis of GC was made within 12 months. Between January 2005 and February 2008, 9764 OGDs were performed. GC was diagnosed in 74 patients (male/female ratio 2.89; median age 76, range 38-95). Nine (12%) patients had EGC. There were no differences in age, sex or symptoms between the EGC and AGC group. Sixty-eight of the 74 patients with GC (92%) presented with alarm symptoms. Ten of the 74 had had an OGD within 12 months before definitive diagnosis; all these were planned because of suspicious lesions. Significantly fewer biopsies were performed at OGDs preceding definitive diagnosis (median 2 (0-10) vs 6 (2-12); p=0.002). False-negative rates of 0% (within 12 months) and 8% (within 3 years) for diagnosis of GC are reassuring, but an inadequate number of biopsies compromises the quality assurance of endoscopy. GC presents without alarm symptoms in <10%.


Neuroprotective effect of masitinib in rats with postischemic stroke.
This study evaluated the therapeutic potential of masitinib, an oral tyrosine kinase inhibitor with activity against c-Kit and platelet-derived growth factor receptors (PDGFR), to reduce ischemic brain area and neurological deficit. Using a well-established filament model of ischemic stroke in rats, the responses to oral treatment with masitinib alone or in combination with recombinant tissue plasminogen activator (rt-PA) were compared to those after rt-PA (10 mg/kg intravenously (i.v.)) monotherapy. In both cases, two doses of masitinib were used--25 or 100 mg/kg, twice per day. Ischemic brain area and the neurological deficit were assessed using the triphenyltetrazolium chloride (TTC) method and behavioral neurological tests, respectively. Masitinib, as a single agent, reduced significantly the infarct size, as compared with the stroke control group. Brain ischemic area decreased from 9.14 to 4.36 % (25 mg/kg) or 2.60 % (100 mg/kg). Moreover, a combined treatment of masitinib with rt-PA produced a stronger effect than the one observed after each of the compound alone. The size of the brain ischemic area (rt-PA 1.67 %) was further reduced to 0.83 or 0.7 % at masitinib doses of 25 and 100 mg/kg, respectively. Masitinib reduced significantly brain ischemia induced by experimental stroke and potentiated the therapeutic effect of rt-PA.


Automated screening for myelodysplastic syndromes through analysis of complete blood count and cell population data parameters.
The diagnosis of myelodysplastic syndromes (MDS) requires a high clinical index of suspicion to prompt bone marrow studies as well as subjective assessment of dysplastic morphology. We sought to determine if data collected by automated hematology analyzers during complete blood count (CBC) analysis might help to identify MDS in a routine clinical setting. We collected CBC parameters (including those for research use only and cell population data) and demographic information in a large (>5,000), unselected sequential cohort of outpatients. The cohort was divided into independent training and test groups to develop and validate a random forest classifier that identifies MDS. The classifier effectively identified MDS and had a receiver operating characteristic area under the curve (AUC) of 0.942. Platelet distribution width and the standard deviation of red blood cell distribution width were the most discriminating variables within the classifier. Additionally, a similar classifier was validated with an additional, independent set of >200 patients from a second institution with an AUC of 0.93. This retrospective study demonstrates the feasibility of identifying MDS in an unselected outpatient population using data routinely collected during CBC analysis with a classifier that has been validated using two independent data sets from different institutions.


Predicting degree of benefit from adjuvant trastuzumab in NSABP trial B-31.
National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31 suggested the efficacy of adjuvant trastuzumab, even in HER2-negative breast cancer. This finding prompted us to develop a predictive model for degree of benefit from trastuzumab using archived tumor blocks from B-31. Case subjects with tumor blocks were randomly divided into discovery (n = 588) and confirmation cohorts (n = 991). A predictive model was built from the discovery cohort through gene expression profiling of 462 genes with nCounter assay. A predefined cut point for the predictive model was tested in the confirmation cohort. Gene-by-treatment interaction was tested with Cox models, and correlations between variables were assessed with Spearman correlation. Principal component analysis was performed on the final set of selected genes. All statistical tests were two-sided. Eight predictive genes associated with HER2 (ERBB2, c17orf37, GRB7) or ER (ESR1, NAT1, GATA3, CA12, IGF1R) were selected for model building. Three-dimensional subset treatment effect pattern plot using two principal components of these genes was used to identify a subset with no benefit from trastuzumab, characterized by intermediate-level ERBB2 and high-level ESR1 mRNA expression. In the confirmation set, the predefined cut points for this model classified patients into three subsets with differential benefit from trastuzumab with hazard ratios of 1.58 (95% confidence interval [CI] = 0.67 to 3.69; P = .29; n = 100), 0.60 (95% CI = 0.41 to 0.89; P = .01; n = 449), and 0.28 (95% CI = 0.20 to 0.41; P < .001; n = 442; P(interaction) between the model and trastuzumab < .001). We developed a gene expression-based predictive model for degree of benefit from trastuzumab and demonstrated that HER2-negative tumors belong to the moderate benefit group, thus providing justification for testing trastuzumab in HER2-negative patients (NSABP B-47).


Auditory Reasoning Skills of Cochlear Implant Users.
This study compared the auditory reasoning skills of school-going children with early and late cochlear implantation and assessed the relationship between auditory reasoning skills, language development, vocabulary knowledge, and communication skills. In this case series study, 90 pre-lingually deaf children aged 7-10 years were assessed. Children were divided into two groups: early-implanted group with children who received cochlear implants before 3 years of age (mean, 23.45; 12-35 months) and late-implanted group with children implanted after 3 years of age (mean, 50.54; 36-84 months). Tests were performed in the auditory-visual condition. Correlational analyses were used to assess the relationships between daily communication skills, language development performances, vocabulary knowledge, and auditory reasoning skills of both the groups. Auditory reasoning skills were better in the early-implanted group than in the late-implanted group (Mann-Whitney U test=518, p<0.05). Language performances of the early-implanted group were significantly better than those of the late-implanted group (receptive language performances: Mann-Whitney U=522, p<0.05; expressive language performances: Mann-Whitney U=552, p<0.05). Stepwise regression analysis showed that expressive language performances, vocabulary knowledge, and chronological age could predict 82% of the variance. Reasoning skills of children with cochlear implants should be supported during the language-learning process.


Association between interleukin-17 gene polymorphisms and the risk of laryngeal cancer in a Chinese population.
IL-17 is associated with the occurrence and development of laryngeal cancer. However, no study has reported the association between IL-17 polymorphisms and laryngeal cancer susceptibility. Therefore, we analyzed the association of three polymorphism loci (rs2275913, 197 G/A; rs3748067, 383 A/G; and rs763780, 7488 T/C) of IL-17A and IL-17F with laryngeal cancer in the Chinese population. A case-control study was performed with 325 patients and 325 controls. Polymorphisms were detected by polymerase chain reaction and sequencing methods. SPSS17.0 software was used for statistical analysis. Allele and genotype frequencies of IL-17A rs2275913 were significantly different between patients and controls (P < 0.05). Frequencies of rs2275913 (197 G/A) AA and GA+AA genotypes compared to the GG genotype were significantly higher in patients than in controls, indicating the association of these genes with laryngeal cancer susceptibility; adjusted OR values were 2.54 (1.50-4.23) and 1.62 (1.19-2.17), respectively. Furthermore, individuals with the GA+AA genotype, compared to the GG genotype, aged ≤60 years, with smoking and alcohol consumption habits, and without a family history of cancer showed a higher cancer risk (OR = 2.74, 95%CI = 1.41-5.23; OR = 2.11, 95%CI = 1.21-3.55; OR = 1.91, 95%CI = 1.02-3.70; OR = 1.99, 95%CI = 1.08-3.39, respectively). In conclusion, the rs2275913 IL-17A (197 G/A) is associated with the incidence and development of laryngeal cancer in the Chinese population, and the AA and GA+AA genotypes harbor a high laryngeal cancer risk.


Broadband and omnidirectional antireflection employing disordered GaN nanopillars.
Disordered GaN nanopillars of three different heights: 300, 550, and 720 nm are fabricated, and demonstrate broad angular and spectral antireflective characteristics, up to an incident angle of 60? and for the wavelength range of lambda=300-1800 nm. An algorithm based on a rigorous coupled-wave analysis (RCWA) method is developed to investigate the correlations between the reflective characteristics and the structural properties of the nanopillars. The broadband and omnidirectional antireflection arises mainly from the refractive-index gradient provided by nanopillars. Calculations show excellent agreement with the measured reflectivities for both s- and p- polarizations.


Generation of radially and azimuthally polarized beams in Yb:YAG laser with intra-cavity lens and birefringent crystal.
We demonstrated the operation of cw diode-pumped Yb:YAG laser in radial or azimuthal polarized (RP or AP) beams using a combination of birefringent uniaxial crystal (c-cut YVO4 or α-BBO) and lens as intra-cavity elements. RP and AP doughnut modes (M2 = 2-2.5, polarization extinction ratio 50-100:1) with output power up to 60 mW were generated. Apart from doughnut modes, RP or AP ring-like off-axis oscillations and multi-ring beams with mixed RP and AP were also observed at the output of this laser scheme. Using intra-cavity short focus lenses with spherical aberrations AP or RP modes of higher orders was obtained. Mechanism of mode selection in the laser is discussed. The large variety of beams with axially symmetric polarizations from the output of the proposed laser scheme may find applications in different fields.


Human listeners are able to classify dog (Canis familiaris) barks recorded in different situations.
The authors investigated whether human listeners could categorize played-back dog (Canis familiaris) barks recorded in various situations and associate them with emotional ratings. Prerecorded barks of a Hungarian herding dog breed (Mudi) provided the sample. Human listeners were asked to rate emotionality of the vocalization and to categorize the situations on the basis of alternative situations provided on a questionnaire. The authors found almost no effect of previous experience with the given dog breed or of owning a dog. Listeners were able to categorize bark situations high above chance level. Emotionality ratings for particular bark samples correlated with peak and fundamental frequency and interbark intervals. The authors did not find a significant effect of tonality (harmonic-to-noise ratio) on either the emotionality rating or situation categorization of the human listeners. Humans' ability to recognize meaning suggests that barks could serve as an effective means of communication between dog and human.


Early Signs of Gut Microbiome Aging: Biomarkers of Inflammation, Metabolism, and Macromolecular Damage in Young Adulthood.
Emerging links between gut microbiota and diseases of aging point to possible shared immune, metabolic, and cellular damage mechanisms, operating long before diseases manifest. We conducted 16S rRNA sequencing of fecal samples collected from a subsample (n = 668) of Add Health Wave V, a nationally representative longitudinal study of adults aged 32-42. An overlapping subsample (n = 345) included whole-blood RNA-seq. We examined associations between fecal taxonomic abundances and dried blood spot-based markers of lipid and glucose homeostasis and C-reactive protein (measured in Wave IV), as well as gene expression markers of inflammation, cellular damage, immune cell composition, and transcriptomic age (measured in Wave V), using Bayesian hierarchical models adjusted for potential confounders. We additionally estimated a co-abundance network between inflammation-related genes and bacterial taxa using penalized Gaussian graphical models. Strong and consistent microbiota associations emerged for HbA1c, glucose, C-reactive protein, and principal components of genes upregulated in inflammation, DNA repair, and reactive oxygen species, with Streptococcus infantis, Pseudomonas spp., and Peptoniphilus as major players for each. This pattern was largely echoed (though attenuated) for immunological cell composition gene sets, and only Serratia varied meaningfully by transcriptomic age. Network co-abundance indicated relationships between Prevotella sp., Bacteroides sp., and Ruminococcus sp. and gut immune/metabolic regulatory activity, and Ruminococcus sp, Dialister, and Butyrivibrio crossotus with balance between Th1 and Th2 inflammation. In conclusion, many common associations between microbiota and major physiologic aging mechanisms are evident in early-mid adulthood and suggest avenues for early detection and prevention of accelerated aging.


Pain and negative affect: evidence the inverse benzodiazepine agonist DMCM inhibits pain and learning in rats.
The anxiogenic DMCM, an inverse benzodiazepine agonist, was used to explore the relationship between negative affective states and pain. Past work suggests that the outcome obtained may depend on both the intensity of the affective state and the way in which pain is inferred. The present study was designed to test the impact of relatively low doses of DMCM on multiple measures of pain reactivity and learning. In experiment 1, systemic injections of 0.00, 0.015, 0.06, and 0.25 mg/kg DMCM were administered before vocalization and tail movements were assessed in response to a gradually incremented shock and radiant heat stimulus. Experiment 2 tested the effects of DMCM on Pavlovian conditioning. DMCM-treated subjects experienced a context paired with an aversive unconditioned stimulus (US) and conditioned freezing was assessed the next day. Experiment 1 showed that DMCM inhibits both a spinal nociceptive reflex (tail-flick to heat) and a supraspinal measure of pain (vocalization to shock). Because these inhibitory effects could reflect a disruption in motor function, experiment 2 employed a remote test based on Pavlovian conditioning. A moderate dose of DMCM undermined learning, implying that the drug decreased the affective impact of the aversive US. DMCM induces hypoalgesia on a wide range of assays. Furthermore, pharmacologically inducing a negative affective state blocks Pavlovian fear conditioning. It is suggested that DMCM induces a state of panic and that this state inhibits pain.


Diagnosis and treatment of an insulinoma in a guinea pig (Cavia porcellus).
A 5-year-old male guinea pig (Cavia porcellus) was examined because of lethargy, weight loss, and episodic neurologic signs, including paddling in lateral recumbency, head tilt, and circling. Prior to initial examination, the animal was treated with corn syrup whenever it appeared lethargic, plus an unknown dosage of sulfadimethoxazole. The animal was thin, with abdominal distention and subtle torticollis. Chemistry panel results documented hypoglycemia (45 mg/dL). Corn syrup was discontinued in favor of a high-fiber formula fed via a syringe. Measurement of blood insulin concentration demonstrated hyperinsulinemia (> 1,440 pmol/L [> 201 μU/L]), with concurrent hypoglycemia (0.6 mmol/L [11 mg/dL]). Diazoxide treatment for presumptive insulinoma was started at a dosage of 5 mg/kg (2.3 mg/lb), p.o., every 12 hours. A blood glucose curve demonstrated persistent hypoglycemia, and the diazoxide dosage was gradually increased to 25 mg/kg (11.4 mg/lb), p.o., every 12 hours. A second glucose curve measurement 12 days later confirmed adequate euglycemic control. Three weeks after the initial diazoxide dosage increase, the animal was reexamined for constipation and abdominal distension and died the following day. Histologic analysis confirmed a pancreatic beta-cell tumor (insulinoma). To the authors' knowledge, this is the first report of premortem diagnosis and treatment of an insulinoma in a guinea pig. This case demonstrates that diazoxide treatment can help achieve euglycemia in hypoglycemic guinea pigs and is a potential treatment option for guinea pigs with insulinoma.


It is never too late: ultra-late recurrence of melanoma with distant metastases.
The authors present the case of a 73-year-old lady presenting with weight loss, personality changes, transient confusion and visual loss, 38 years after initial surgical excision of a melanoma of the neck. CT and MRI of the brain showed cerebral metastases and positron emission tomography (PET)-CT showed an additional fludeoxyglucose avid lesion in the lung, which was biopsied. Histology confirmed metastatic malignant melanoma. She declined whole brain radiotherapy in favour of best supportive care and died 4 months after diagnosis. Life-long vigilance among patients with previous melanoma and awareness among physicians are necessary if late recurrences are to be recognised early, and outcomes improved. New imaging techniques including PET-CT may be helpful in diagnosing and staging melanoma recurrence. Treatment options for patients presenting with distant metastases are limited and the prognosis remains poor.


Optimum sampling of Fresnel transforms.
The opportunity to process signals in domains other than the time or frequency domains arises naturally in coherently illuminated optical systems that produce Fourier transforms. It is well known that N samples are sufficient to represent the information content in the object, image, and Fourier planes. We extend these results to show that we can accurately represent the intensity signal in any Fresnel plane of a coherently illuminated optical system with exactly N samples, provided that we use a specified nonuniform sampling technique.


A novel, potent dual inhibitor of the leukocyte proteases cathepsin G and chymase: molecular mechanisms and anti-inflammatory activity in vivo.
Certain leukocytes release serine proteases that sustain inflammatory processes and cause disease conditions, such as asthma and chronic obstructive pulmonary disease. We identified beta-ketophosphonate 1 (JNJ-10311795; RWJ-355871) as a novel, potent dual inhibitor of neutrophil cathepsin G (K(i) = 38 nm) and mast cell chymase (K(i) = 2.3 nm). The x-ray crystal structures of 1 complexed with human cathepsin G (1.85 A) and human chymase (1.90 A) reveal the molecular basis of the dual inhibition. Ligand 1 occupies the S(1) and S(2) subsites of cathepsin G and chymase similarly, with the 2-naphthyl in S(1), the 1-naphthyl in S(2), and the phosphonate group in a complex network of hydrogen bonds. Surprisingly, however, the carboxamido-N-(naphthalene-2-carboxyl)piperidine group is found to bind in two distinct conformations. In cathepsin G, this group occupies the hydrophobic S(3)/S(4) subsites, whereas in chymase, it does not; rather, it folds onto the 1-naphthyl group of the inhibitor itself. Compound 1 exhibited noteworthy anti-inflammatory activity in rats for glycogen-induced peritonitis and lipopolysaccharide-induced airway inflammation. In addition to a marked reduction in neutrophil influx, 1 reversed increases in inflammatory mediators interleukin-1alpha, interleukin-1beta, tissue necrosis factor-alpha, and monocyte chemotactic protein-1 in the glycogen model and reversed increases in airway nitric oxide levels in the lipopolysaccharide model. These findings demonstrate that it is possible to inhibit both cathepsin G and chymase with a single molecule and suggest an exciting opportunity in the treatment of asthma and chronic obstructive pulmonary disease.


In vitro assembly of a complete, pentaglycine interpeptide bridge containing cell wall precursor (lipid II-Gly5) of Staphylococcus aureus.
Staphylococcus aureus peptidoglycan is cross-linked via a characteristic pentaglycine interpeptide bridge. Genetic analysis had identified three peptidyltransferases, FemA, FemB and FemX, to catalyse the formation of the interpeptide bridge, using glycyl t-RNA as Gly donor. To analyse the pentaglycine bridge formation in vitro, we purified the potential substrates for FemA, FemB and FemX, UDP-MurNAc-pentapeptide, lipid I and lipid II and the staphylococcal t-RNA pool, as well as His-tagged Gly-tRNA-synthetase and His-tagged FemA, FemB and FemX. We found that FemX used lipid II exclusively as acceptor for the first Gly residue. Addition of Gly 2,3 and of Gly 4,5 was catalysed by FemA and FemB, respectively, and both enzymes were specific for lipid II-Gly1 and lipid II-Gly3 as acceptors. None of the FemABX enzymes required the presence of one or two of the other Fem proteins for activity; rather, bridge formation was delayed in the in vitro system when all three enzymes were present. The in vitro assembly system described here will enable detailed analysis of late, membrane-associated steps of S. aureus peptidoglycan biosynthesis.


Systemic BCNU enhances the efficacy of local delivery of a topoisomerase I inhibitor against malignant glioma.
To investigate the ability of systemically delivered BCNU to enhance the activity of either systemically delivered irinotecan (CPT-11) or locally delivered camptothecin from a biodegradable polymer for treatment of an intracranial 9L gliosarcoma. We used a single systemic dose of BCNU on treatment day 1 in combination with systemic doses of CPT-11 on treatment days 1-5 and 8-12 against an intracranial rat 9L gliosarcoma model implanted into female Fischer 344 rats. We also used the same systemic dose of BCNU given on treatment day 1, followed by a local dose of a 20% loaded camptothecin biodegradable polymer implanted on the same day. Two doses of CPT-11 (10 and 60 mg/kg) were delivered systemically against intracranial 9L. Neither dose showed an increase in survival compared to controls ( P>0.2 for 10 mg/kg and P=0.17 for 60 mg/kg). Systemic delivery of CPT-11 (10 mg/kg per day) in combination with systemic BCNU (15 mg/kg) did not show a significant effect on survival compared to systemic BCNU alone ( P>0.2), even at the maximally tolerated systemic dose of CPT-11 (60 mg/kg per day; P=0.06). The combination of systemic BCNU (15 mg/kg) and intracranial delivery of camptothecin (20% loaded polymer), however, significantly extended survival compared to systemic BCNU alone ( P<0.001) and compared to intracranial delivery of camptothecin alone ( P=0.01). In a 9L gliosarcoma model, systemic delivery of CPT-11 showed no benefit in survival when delivered alone or in combination with systemic BCNU, because CPT-11 is unable to cross the blood-brain barrier in cytotoxic levels. When cytotoxic levels of a topoisomerase I inhibitor are delivered directly to the brain tumor via a biodegradable polymer, however, the systemic delivery of the alkylating agent BCNU significantly enhances the antitumor effects of camptothecin in a 9L gliosarcoma model.


Bridging the gap: a review of dose investigations in paediatric investigation plans.
In the EU, development of new medicines for children should follow a prospectively agreed paediatric investigation plan (PIP). Finding the right dose for children is crucial but challenging due to the variability of pharmacokinetics across age groups and the limited sample sizes available. We examined strategies adopted in PIPs to support paediatric dosing recommendations to identify common assumptions underlying dose investigations and the attempts planned to verify them in children. We extracted data from 73 PIP opinions recently adopted by the Paediatric Committee of the European Medicines Agency. These opinions represented 79 medicinal development programmes and comprised a total of 97 dose investigation studies. We identified the design of these dose investigation studies, recorded the analyses planned and determined the criteria used to define target doses. Most dose investigation studies are clinical trials (83 of 97) that evaluate a single dosing rule. Sample sizes used to investigate dose are highly variable across programmes, with smaller numbers used in younger children (< 2 years). Many studies (40 of 97) do not pre-specify a target dose criterion. Of those that do, most (33 of 57 studies) guide decisions using pharmacokinetic data alone. Common assumptions underlying dose investigation strategies include dose proportionality and similar exposure-response relationships in adults and children. Few development programmes pre-specify steps to verify assumptions in children. There is scope for the use of Bayesian methods as a framework for synthesizing existing information to quantify prior uncertainty about assumptions. This process can inform the design of optimal drug development strategies.


An intramolecular interaction between SH2-kinase linker and kinase domain is essential for the catalytic activity of protein-tyrosine kinase-6.
Protein-tyrosine kinase-6 (PTK6, also known as Brk) is a non-receptor tyrosine kinase that contains SH3, SH2, and catalytic (Kinase) domains. We have identified an intramolecular interaction between the linker (Linker) region connecting the SH2 and Kinase domains and the Kinase domain. Residue Trp-184 within the Linker region is essential for the Linker-Kinase interaction but not for the Linker-SH3 interaction. A recombinant PTK6 Kinase domain connected to the Linker region had catalytic activity in terms of autophosphorylation, phosphorylation of a PTK6 substrate, BKS, and phosphorylation of an oligopeptide substrate, whereas the Kinase domain itself, or one connected to a Linker region containing a W184A substitution, did not. The introduction of the W184A mutation into PTK6 also abrogated autophosphorylation and phosphorylation of another PTK6 substrate, Sam68, as well as phosphorylation of intracellular proteins. It also abolished the ability of PTK6 to promote proliferation and prevent apoptosis of HEK 293 cells, as well as to permit anchorage-independent colony formation. Therefore, unlike Src family members, in which the Linker-Kinase interaction inhibits catalytic activity, in PTK6 this interaction has an essential positive role.


Anaesthesia and high altitude: a history.
During an expedition to climb Everest in 1933, expedition doctor Raymond Greene administered an open-drop chloroform anaesthetic to a Tibetan patient at an altitude of more than 14,000 feet. The patient's subsequent apparent cardiopulmonary arrest has long been attributed to the effects of altitude on anaesthetic delivery. However, anaesthetics can be safely administered at a wide variety of altitudes by adequately trained and experienced anaesthetists. The problems may have arisen from an inadequate depth of anaesthesia consequent to decreased chloroform vaporisation in a cold environment, Greene's concern about potential depression of ventilation and the contemporary lack of a precise approach to assessing depth of anaesthesia.


Cohort study of diet, lifestyle, and prostate cancer in Adventist men.
Dietary and lifestyle characteristics were evaluated in relation to subsequent prostatic cancer risk in a cohort of approximately 14,000 Seventh-day Adventist men who completed a detailed lifestyle questionnaire in 1976 and who were monitored for cancer incidence until the end of 1982. During the 6-year follow-up period, 180 histologically confirmed prostatic cancers were detected among some 78,000 man-years of follow-up. Increasing educational attainment was associated with significantly decreased risk of prostate cancer in this study; age at first marriage was also inversely associated with risk, although this was not significant. There was no relationship between body mass index (as measured by Quetelet's Index) and risk. A history of prostate "trouble" was associated with a 60% increase in risk which was highly significant. Although there were suggestive relationships between increasing animal product consumption and increased risk, these results did not persist after accounting for the influence of fruit and vegetable consumption. Nor was exposure to the vegetarian lifestyle during the childhood years associated with alterations in subsequent risk. However, increasing consumption of beans, lentils and peas, tomatoes, raisin, dates, and other dried fruit were all associated with significantly decreased prostate cancer risk.


Blau syndrome with a rare mutation in exon 9 of NOD2 gene.
Blau syndrome is an autosomal dominant rare disease caused by mutations in NOD2 gene. Less than 200 patients published with Blau Syndrome Worldwide. We reported a 41-year old female Turkish patient diagnosed as Blau syndrome. Granulomatous dermatitis and severe headache, as well as recurrent chest and pelvic pain have been present since she was 8 years old. Arthritis started when she was teenage, hypertension diagnosed when she was 20 and other symptoms also occurred during the lifetime (severe preeclampsia, ischemic stroke, recurrent hemiparesis, recurrent-transient-vision-loss and renal-artery-stenosis). Genomic DNA was isolated from peripheral blood and 12 genes sequenced in Autoinflammatory panel on IonTorrent-S5-NGS platform with Parseq-VariFind™AIPassay. NGS analysis showed 107 variants in in the index case, mainly benign with no strong association with Blau syndrome. Additionally, we identified one very rare missense mutation in NOD2 gene (c2803G>A, p.Val935Met) and in silico assessment of the mutation indicated possible pathogenic significance and strong association with Blau syndrome. In addition, we analyzed family members of the index case and identified the same mutation in NOD2 gene. The segregation analysis shows the presence of the same mutant allele in NOD2 gene in the index case affected sister, as well as in her son with arthralgia, while in her non affecter brother we didn't detect the Val935Met mutation in NOD2 gene. Blau Syndrome is known as a very rare disease, mainly caused by mutations in NOD2 gene. Missense mutation diagnosed in our case could be responsible for the phenotype of the index case. Our results indicate the importance of NGS testing and its major role in the detection of rare mutations that may responsible for the onset of autoinflammatory disorders.


Ramipril and experimental vein graft intimal hyperplasia.
Angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce the intimal proliferation in animal models of arterial angioplasty and vein bypass grafting. This study examines the effect of high-dose ramipril, an ACE inhibitor that does not contain a sulfhydryl group, on the development of intimal hyperplasia in experimental vein bypass grafts. Twenty New Zealand White rabbits underwent common carotid interposition bypass grafting. Twelve were treated with ramipril (2 mg/kg/day; po) five days prior to surgery and thereafter until harvest. The remaining 8 animals were used as controls. Vein grafts were harvested at twenty-eight days by pressure fixation (80 mmHg). The grafts were sectioned into proximal, middle, and distal thirds, and the thickness of the intima and the media and the area of the lumen from each segment were determined by videomorphometry. The effect of ramipril on the [H3]thymidine incorporation into DNA of serum-stimulated smooth muscle cells (culture passage 6 to 12) was also assessed. There was a 50% mortality rate in the rabbits that received ramipril, and this was assumed to be related to the high dose of the drug. Ramipril treatment reduced mean vein graft intimal area by 34% (P > 0.05), but this was accompanied by an increase of 73% in the mean medial area of the vein grafts as compared with controls. These changes resulted in a decrease in the mean intimal ratio (intima/[intima + media]) by 39% in the ramipril group as compared with controls. Ramipril did not inhibit [H3]thymidine incorporation into DNA of serum-stimulated smooth muscle cells.(ABSTRACT TRUNCATED AT 250 WORDS)


CD45RA Distinguishes CD4+CD25+CD127-/low TSDR Demethylated Regulatory T Cell Subpopulations With Differential Stability and Susceptibility to Tacrolimus-Mediated Inhibition of Suppression.
Adoptive transfer of forkhead box protein (FOX)3 regulatory T (Treg) cells offers a promising strategy to reduce damage to an allograft by the recipient's immune system. Identification of cell surface markers sufficient to purify Treg cells expanded ex vivo to remove cellular contaminants requires optimization. Furthermore, the expanded Treg must be able to survive, expand, and suppress in allograft recipients exposed to immunosuppressants, such as tacrolimus (TAC). Reduced CD127 expression enhances identification of Treg in the human CD4CD25 population. CD45RA expression identifies naive CD4CD25 Treg with an enhanced stability of Treg phenotype. We combine an analysis of CD45RA, CD25, and CD127 expression to identify subpopulations of CD4CD127CD25 cells. Regulatory T cells were sorted according to expression of CD25 and CD45RA and expanded in the presence of a physiological relevant concentration of TAC. Regulatory T cell-specific demethylation region (TSDR) demethylation, FOXP3 expression, and suppression were analyzed. CD4CD127CD25CD45RA Treg cells had a stable TSDR demethylated FOXP3 phenotype after expansion whereas CD4CD127CD25CD45RA Treg cell lost the TSDR demethylated phenotype. CD45RA Treg had a greater capacity to suppress after expansion with TAC. Although CD45RA Treg retained a greater suppressive capacity when expanded with TAC, the marked loss of the TSDR demethylated status highlights the potential for loss of stability of these cells in transplant recipients treated with TAC based immunosuppression. We show that a population of CD4CD127CD45RA Regulatory T cell may offer the best compromise between susceptibility to loss of suppression when exposed to TAC and maintenance of a TSDR demethylated phenotype following in vitro expansion.


International survey on attitudes toward ethics in health technology assessment: An exploratory study.
The objective of this exploratory study was to survey international health technology assessment (HTA) professionals to determine attitudes toward ethics in HTA. An exploratory, quantitative, cross-sectional study design was developed. The sample population (n = 636) was selected from authors of the 206 articles published in the International Journal of Technology Assessment in Health Care between 2005 and 2007. A survey instrument was piloted and e-mailed. The response rate was low (n = 104; 16.4 percent). Respondents were primarily middle-aged (46 ± 11 years) male (62 percent) health professionals from Western countries (n = 92; 88.5 percent), with a mean of 10 (± 6 years) years of HTA experience. Although at least 90 percent of respondents agreed that healthcare decisions involved value judgments and that ethical analysis was important to HTA, respondents were divided as to whether normative (n = 45; 44.6 percent) or descriptive (n = 38; 37.6 percent) ethical recommendations were necessary. Most respondents (n = 83; 81.4 percent) believed that HTA should include citizen participation, but two thirds (n = 67; 67.0 percent) agreed that the final decision should be restricted to decision makers. A majority of respondents thought that ethical analysis could be discussed anywhere within the HTA process, either by an expert trained in ethics (n = 62; 60.8 percent) or by an external consultant (n = 80; 78.4 percent). This study showed that ethical discourse in HTA is constrained by practical considerations, which serves to limit moral inquiry. To increase ethical analysis, a positive attitude toward ethics needs to be fostered within the HTA community.


Multi locus analysis of Pristionchus pacificus on La Réunion Island reveals an evolutionary history shaped by multiple introductions, constrained dispersal events and rare out-crossing.
Pristionchus pacificus, recently established as a model organism in evolutionary biology, is a cosmopolitan nematode that has a necromenic association with scarab beetles. The diverse array of host beetle species and habitat types occupied by P. pacificus make it a good model for investigating local adaptation to novel environments. Presence of P. pacificus on La Réunion Island, a young volcanic island with a dynamic geological history and a wide variety of ecozones, facilitates such investigation in an island biogeographic setting. Microsatellite data from 20 markers and 223 strains and mitochondrial sequence data from 272 strains reveal rich genetic diversity among La Réunion P. pacificus isolates, shaped by differentially timed introductions from diverse sources and in association with different beetle species. Distinctions between volcanic zones and between arid western and wet eastern climatic zones have likely limited westward dispersal of recently colonized lineages and maintained a genetic distinction between eastern and western clades. The highly selfing lifestyle of P. pacificus contributes to the strong fine-scale population structure detected, with each beetle host harbouring strongly differentiated assemblages of strains. Periodic out-crossing generates admixture between genetically diverse lineages, creating a diverse array of allelic combinations likely to increase the evolutionary potential of the species and facilitate adaptation to local environments and beetle hosts.


Alcohol consumption, alcohol-related problems, problem drinking, and socioeconomic status.
In general, a lower socioeconomic status (SES) is related to a lower health status, more health problems, and a shorter life expectancy. Although causal relations between SES and health are unclear, lifestyle factors play an intermediate role. The purpose of the present study was to obtain more insight into the relation between SES, alcohol consumption, alcohol-related problems, and problem drinking, through a general population survey among 8000 people in Rotterdam. Odds ratios were calculated using educational level as independent, and alcohol consumption, alcohol-related problems, and problem drinking as dependent variables. Abstinence decreased significantly by increasing educational level for both sexes. For men, excessive drinking, and notably very excessive drinking, was more prevalent in the lowest educational group. For women, no significant relation between educational level and prevalence of excessive drinking was found. After controlling for differences in drinking behaviour, among men the prevalence of 'psychological dependence' and 'social problems' was higher in intermediate educational groups, whereas prevalence of 'drunkenness' was lower in intermediate educational groups. For women, a negative relation was found between educational level and 'psychological dependence'; prevalence of 'symptomatic drinking' was higher in the lowest educational group. Prevalence of problem drinking was not related to educational level in either sex. It is concluded that differences exist between educational levels with respect to abstinence, but only limited differences were found with respect to excessive drinking. Furthermore, there is evidence for higher prevalences of alcohol-related problems in lower educational levels, after controlling for differences in drinking behaviour, in both sexes.


Associations between residual feed intake and apparent nutrient digestibility, in vitro methane-producing activity, and volatile fatty acid concentrations in growing beef cattle1.
The objectives of this study were to examine the relationship between residual feed intake (RFI) and DM and nutrient digestibility, in vitro methane production, and volatile fatty acid (VFA) concentrations in growing beef cattle. Residual feed intake was measured in growing Santa Gertrudis steers (Study 1; n = 57; initial BW = 291.1 ± 33.8 kg) and Brangus heifers (Study 2; n = 468; initial BW = 271.4 ± 26.1 kg) fed a high-roughage-based diet (ME = 2.1 Mcal/kg DM) for 70 d in a Calan-gate feeding barn. Animals were ranked by RFI based on performance and feed intake measured from day 0 to 70 (Study 1) or day 56 (Study 2) of the trial, and 20 animals with the lowest and highest RFI were identified for subsequent collections of fecal and feed refusal samples for DM and nutrient digestibility analysis. In Study 2, rumen fluid and feces were collected for in vitro methane-producing activity (MPA) and VFA analysis in trials 2, 3, and 4. Residual feed intake classification did not affect BW or BW gain (P > 0.05), but low-RFI steers and heifers both consumed 19% less (P < 0.01) DMI compared with high-RFI animals. Steers with low RFI tended (P < 0.1) to have higher DM digestibility (DMD) compared with high-RFI steers (70.3 vs. 66.5 ± 1.6% DM). Heifers with low RFI had 4% higher DMD (76.3 vs. 73.3 ± 1.0% DM) and 4 to 5% higher (P < 0.01) CP, NDF, and ADF digestibility compared with heifers with high RFI. Low-RFI heifers emitted 14% less (P < 0.01) methane (% GE intake; GEI) calculated according to Blaxter and Clapperton (1965) as modified by Wilkerson et al. (1995), and tended (P = 0.09) to have a higher rumen acetate:propionate ratio than heifers with high RFI (GEI = 5.58 vs. 6.51 ± 0.08%; A:P ratio = 5.02 vs. 4.82 ± 0.14%). Stepwise regression analysis revealed that apparent nutrient digestibilities (DMD and NDF digestibility) for Study 1 and Study 2 accounted for an additional 8 and 6%, respectively, of the variation in intake unaccounted for by ADG and mid-test BW0.75. When DMD, NDF digestibility, and total ruminal VFA were added to the base model for Study 2, trials 2, 3, and 4, the R2 increased from 0.33 to 0.47, explaining an additional 15% of the variation in DMI unrelated to growth and body size. On the basis of the results of these studies, differences in observed phenotypic RFI in growing beef animals may be a result of inter-animal variation in apparent nutrient digestibility and ruminal VFA concentrations.


A key enzyme in the biogenesis of lysosomes is a protease that regulates cholesterol metabolism.
Mucolipidosis II is a severe lysosomal storage disorder caused by defects in the α and β subunits of the hexameric N-acetylglucosamine-1-phosphotransferase complex essential for the formation of the mannose 6-phosphate targeting signal on lysosomal enzymes. Cleavage of the membrane-bound α/β-subunit precursor by an unknown protease is required for catalytic activity. Here we found that the α/β-subunit precursor is cleaved by the site-1 protease (S1P) that activates sterol regulatory element-binding proteins in response to cholesterol deprivation. S1P-deficient cells failed to activate the α/β-subunit precursor and exhibited a mucolipidosis II-like phenotype. Thus, S1P functions in the biogenesis of lysosomes, and lipid-independent phenotypes of S1P deficiency may be caused by lysosomal dysfunction.


Impaired degradation followed by enhanced recycling of epidermal growth factor receptor caused by hypo-phosphorylation of tyrosine 1045 in RBE cells.
Since cholangiocarcinoma has a poor prognosis, several epidermal growth factor receptor (EGFR)-targeted therapies with antibody or small molecule inhibitor treatment have been proposed. However, their effect remains limited. The present study sought to understand the molecular genetic characteristics of cholangiocarcinoma related to EGFR, with emphasis on its degradation and recycling. We evaluated EGFR expression and colocalization by immunoblotting and immunofluorescence, cell surface EGFR expression by fluorescence-activated cell sorting (FACS), and EGFR ubiquitination and protein binding by immunoprecipitation in the human cholangiocarcinoma RBE and immortalized cholangiocyte MMNK-1 cell lines. Monensin treatment and Rab11a depletion by siRNA were adopted for inhibition of EGFR recycling. Upon stimulation with EGF, ligand-induced EGFR degradation was impaired and the expression of phospho-tyrosine 1068 and phospho-p44/42 MAPK was sustained in RBE cells as compared with MMNK-1 cells. In RBE cells, the process of EGFR sorting for lysosomal degradation was blocked at the early endosome stage, and non-degradated EGFR was recycled to the cell surface. A disrupted association between EGFR and the E3 ubiquitin ligase c-Cbl, as well as hypo-phosphorylation of EGFR at tyrosine 1045 (Tyr1045), were also observed in RBE cells. In RBE cells, up-regulation of EGFR Tyr1045 phosphorylation is a potentially useful molecular alteration in EGFR-targeted therapy. The combination of molecular-targeted therapy determined by the characteristics of individual EGFR phosphorylation events and EGFR recycling inhibition show promise in future treatments of cholangiocarcinoma.


Alpine climate treatment of atopic dermatitis: a systematic review.
Climate therapy has been used for decades in the treatment of atopic dermatitis (AD), but evidence of its effectiveness has not yet been assessed systematically. A systematic literature search in Medline, Embase, and the Cochrane library was performed to identify all original studies concerning alpine climate treatment. The risk of bias of individual studies was assessed following the Cochrane Handbook, and level of evidence was rated using GRADE guidelines. Fifteen observational studies were included concerning 40 148 patients. Four studies concerning 2670 patients presented follow-up data over a period of 1 year. Disease activity decreased in the majority of patients during treatment (96% of n = 39 006) and 12-month follow-up (64% of n = 2670). Topical corticosteroid use could often be reduced or stopped during treatment (82% of n = 1178) and during 12-month follow-up (72% of n = 3008). Quality assessment showed serious study limitations, therefore resulting in a very low level of evidence for the described outcomes. Randomized controlled trials designed with a follow-up period including well-defined patient populations, detailed description and measurement of applied interventions during climate therapy and using validated outcomes including cost-effectiveness parameters, are required to improve the evidence for alpine climate therapy as an effective treatment for patients with AD.


Stretching single talin rod molecules activates vinculin binding.
The molecular mechanism by which a mechanical stimulus is translated into a chemical response in biological systems is still unclear. We show that mechanical stretching of single cytoplasmic proteins can activate binding of other molecules. We used magnetic tweezers, total internal reflection fluorescence, and atomic force microscopy to investigate the effect of force on the interaction between talin, a protein that links liganded membrane integrins to the cytoskeleton, and vinculin, a focal adhesion protein that is activated by talin binding, leading to reorganization of the cytoskeleton. Application of physiologically relevant forces caused stretching of single talin rods that exposed cryptic binding sites for vinculin. Thus in the talin-vinculin system, molecular mechanotransduction can occur by protein binding after exposure of buried binding sites in the talin-vinculin system. Such protein stretching may be a more general mechanism for force transduction.


Evaluating N-benzylgalactonoamidines as putative transition state analogs for β-galactoside hydrolysis.
Experimental evidence is provided for p-methylbenzyl-D-galactonoamidine to function as a true transition state analog for the enzymatic hydrolysis of aryl-β-D-galactopyranosides by β-galactosidase (A. oryzae). The compound exhibits inhibition constants in the low nanomolar concentration range (12-56 nM) for a selection of substrates. Along these lines, a streamlined synthetic method based on phase-transfer catalysis was optimized to afford the required variety of new aryl-β-D-galactopyranosides. Last, the stability of the galactonoamidines under the assay conditions was confirmed.


Accurate prediction of hot spot residues through physicochemical characteristics of amino acid sequences.
Hot spot residues of proteins are fundamental interface residues that help proteins perform their functions. Detecting hot spots by experimental methods is costly and time-consuming. Sequential and structural information has been widely used in the computational prediction of hot spots. However, structural information is not always available. In this article, we investigated the problem of identifying hot spots using only physicochemical characteristics extracted from amino acid sequences. We first extracted 132 relatively independent physicochemical features from a set of the 544 properties in AAindex1, an amino acid index database. Each feature was utilized to train a classification model with a novel encoding schema for hot spot prediction by the IBk algorithm, an extension of the K-nearest neighbor algorithm. The combinations of the individual classifiers were explored and the classifiers that appeared frequently in the top performing combinations were selected. The hot spot predictor was built based on an ensemble of these classifiers and to work in a voting manner. Experimental results demonstrated that our method effectively exploited the feature space and allowed flexible weights of features for different queries. On the commonly used hot spot benchmark sets, our method significantly outperformed other machine learning algorithms and state-of-the-art hot spot predictors. The program is available at http://sfb.kaust.edu.sa/pages/software.aspx.


The PredictAD project: development of novel biomarkers and analysis software for early diagnosis of the Alzheimer's disease.
Alzheimer's disease (AD) is the most common cause of dementia affecting 36 million people worldwide. As the demographic transition in the developed countries progresses towards older population, the worsening ratio of workers per retirees and the growing number of patients with age-related illnesses such as AD will challenge the current healthcare systems and national economies. For these reasons AD has been identified as a health priority, and various methods for diagnosis and many candidates for therapies are under intense research. Even though there is currently no cure for AD, its effects can be managed. Today the significance of early and precise diagnosis of AD is emphasized in order to minimize its irreversible effects on the nervous system. When new drugs and therapies enter the market it is also vital to effectively identify the right candidates to benefit from these. The main objective of the PredictAD project was to find and integrate efficient biomarkers from heterogeneous patient data to make early diagnosis and to monitor the progress of AD in a more efficient, reliable and objective manner. The project focused on discovering biomarkers from biomolecular data, electrophysiological measurements of the brain and structural, functional and molecular brain images. We also designed and built a statistical model and a framework for exploiting these biomarkers with other available patient history and background data. We were able to discover several potential novel biomarker candidates and implement the framework in software. The results are currently used in several research projects, licensed to commercial use and being tested for clinical use in several trials.


Adherence to antiretroviral therapy and clinical outcomes among young adults reporting high-risk sexual behavior, including men who have sex with men, in coastal Kenya.
African men who have sex with men (MSM) face significant stigma and barriers to care. We investigated antiretroviral therapy (ART) adherence among high-risk adults, including MSM, participating in a clinic-based cohort. Survival analysis was used to compare attrition across patient groups. Differences in adherence, weight gain, and CD4 counts after ART initiation were assessed. Among 250 HIV-1-seropositive adults, including 108 MSM, 15 heterosexual men, and 127 women, patient group was not associated with attrition. Among 58 participants who were followed on ART, 40 % of MSM had less than 95 % adherence, versus 28.6 % of heterosexual men and 11.5 % of women. Although MSM gained less weight after ART initiation than women (adjusted difference -3.5 kg/year), CD4 counts did not differ. More data are needed on barriers to adherence and clinical outcomes among African MSM, to ensure that MSM can access care and derive treatment and prevention benefits from ART.


Countdown to 2015 for maternal, newborn, and child survival: the 2008 report on tracking coverage of interventions.
The Countdown to 2015 for Maternal, Newborn, and Child Survival initiative monitors coverage of priority interventions to achieve the Millennium Development Goals (MDG) for reduction of maternal and child mortality. We aimed to report on 68 countries which have 97% of maternal and child deaths worldwide, and on 22 interventions that have been proven to improve maternal, newborn, and child survival. We selected countries with high rates of maternal and child deaths, and interventions with the most potential to avert such deaths. We analysed country-specific data for maternal and child mortality and coverage of selected interventions. We also tracked cause-of-death profiles; indicators of nutritional status; the presence of supportive policies; financial flows to maternal, newborn, and child health; and equity in coverage of interventions. Of the 68 priority countries, 16 were on track to meet MDG 4. Of these, seven had been on track in 2005 when the Countdown initiative was launched, three (including China) moved into the on-track category in 2008, and six were included in the Countdown process for the first time in 2008. Trends in maternal mortality that would indicate progress towards MDG 5 were not available, but in most (56 of 68) countries, maternal mortality was high or very high. Coverage of different interventions varied widely both between and within countries. Interventions that can be routinely scheduled, such as immunisation and antenatal care, had much higher coverage than those that rely on functional health systems and 24-hour availability of clinical services, such as skilled or emergency care at birth and care of ill newborn babies and children. Data for postnatal care were either unavailable or showed poor coverage in almost all 68 countries. The most rapid increases in coverage were seen for immunisation, which also received significant investment during this period. Rapid progress is possible, but much more can and must be done. Focused efforts will be needed to improve coverage, especially for priorities such as contraceptive services, care in childbirth, postnatal care, and clinical case management of illnesses in newborn babies and children.


DNA sequence and transcription of a DNA minicircle isolated from male-fertile sugar beet mitochondria.
A minicircle consisting of 1440 bp was isolated from male fertile sugar beet mitochondria. The entire nucleotide sequence of the minicircle was determined. There are several stop codons in all three reading frames and it is therefore unlikely that the minicircle codes for a polypeptide product. However, the minicircle is transcribed yielding a major RNA product consisting of 850 bases in addition to two very minor RNA products of 1100 and 950 bases, respectively. All three RNA products are transcribed from the same strand. The starting point for transcription of the major RNA product was determined by S1 nuclease protection analysis.


Effect of sampling on real ocular aberration measurements.
The minimum number of samples necessary to fully characterize the aberration pattern of the eye is a question under debate in the clinical as well as the scientific community. We performed repeated measurements of ocular aberrations in 12 healthy nonsurgical human eyes and in 3 artificial eyes, using different sampling patterns (hexagonal, circular, and rectangular with 19 to 177 samples, and 3 radial patterns with 49 sample coordinates corresponding to zeros of the Albrecht, Jacobi, and Legendre functions). For each measurement set we computed two different metrics based on the root-mean-square (RMS) of difference maps (RMS_Diff) and the proportional change in the wavefront (W%). These metrics are used to compare wavefront estimates as well as to summarize results across eyes. We used computer simulations to extend our results to "abnormal eyes" (keratoconic, post-LASIK, and post-radial keratotomy eyes). We found that the spatial distribution of the samples can be more important than the number of samples for both our measured as well as our simulated "abnormal" eyes. Experimentally, we did not find large differences across patterns except, as expected, for undersampled patterns.


Synthesis and evaluation of N-alkyl-beta-D-glucosylamines on the growth of two wood fungi, Coriolus versicolor and Poria placenta.
Various glucosylamines were synthesized from glucose and different alkyl amine compounds. These amino compounds are beta-D-glucopyranosylamine (GPA), N-ethyl-beta-D-glucopyranosylamine (EtGPA), N-butyl-beta-D-glucopyranosylamine (BuGPA), N-hexyl-beta-D-glucopyranosylamine (HeGPA), N-octyl-beta-D-glucopyranosylamine (OcGPA), N-dodecyl-beta-D-glucopyranosylamine (DoGPA), N-(2-hydroxyethyl)-beta-D-glucopyranosylamine (HEtGPA) and N,N-di(2-hydroxyethyl)-beta-D-glucopyranosylamine (DHEtGPA). They were tested for their antifungal activity against the growth of Coriolus versicolor and Poria placenta. An improvement of the antifungal activity with the increase of alkyl chain length was observed. DoGPA exhibited the best antifungal activity against both strains. It completely inhibited the fungal growth at 0.01x10(-3)molmL(-1) and 0.0075x10(-3)molmL(-1) for C. versicolor and P. placenta, respectively. For other glucosylamines higher concentrations were needed for complete inhibition of fungi.


Setting up a pragmatic clinical trial in a low-resource setting: A qualitative assessment of GoLBeT, a trial of podoconiosis management in Northern Ethiopia.
Clinical trials are often perceived as being expensive, difficult and beyond the capacity of healthcare workers in low-resource settings. However, in order to improve healthcare coverage, the World Health Organization (WHO) World Health Report 2013 stated that all countries need to become generators as well as recipients of data. This study is a methodological examination of the steps and processes involved in setting up the Gojjam Lymphoedema Best Practice Trial (GoLBeT; ISRCTN67805210), a highly pragmatic clinical trial conducted in northern Ethiopia. Challenges to the trial and strategies used to deal with them were explored, together with the reasons for delays. Qualitative research methods were used to analyse emails and reports from the period between trial inception and recruitment. This analysis was complemented by interviews with key informants from the trial operational team. The Global Health Research Process Map was used as a framework against which to compare the steps involved in setting up the trial. A mini-group discussion was conducted with the trial operational team after study completion for reflection and further recommendations. This study showed that the key areas of difficulty in setting up and planning this trial were: the study design, that is, deciding on the study endpoint, where and how best to measure it, and assuring statistical power; recruitment and appropriate training of staff; planning for data quality; and gaining regulatory approvals. Collaboration, for example with statisticians, the trial steering committee, the study monitors, and members of the local community was essential to successfully setting up the trial. Lessons learnt from this trial might guide others planning pragmatic trials in settings where research is not common, allowing them to anticipate possible challenges and address them through trial design, planning and operational delivery. We also hope that this example might encourage similar pragmatic studies to be undertaken. Such studies are rarely undertaken or locally led, but are an accessible and efficient way to drive improved outcomes in public health.


SU-E-T-281: Secondary Light-Ions in Carbon-Ion Therapy: A GEANT4 Simulation of LET and Dose Contributions.
The purpose of this investigation was to reveal the dosimetric characteristics and contributions of the secondary light ions produced from carbon-ion beams in water via a GEANT4 simulation. GEANT4 low energy electromagnetic physics processes were used for all ions. The hadronic interactions of protons and neutrons are simulated using low energy elastic interactions while inelastic scattering is simulated with a binary cascade (BIC) model. Other inelastic light-ion interactions are being simulated through the application of a quasi-molecular dynamics (QMD) model. A 27 liter cubic water phantom consisting of 3000 packed rectangular detector sheets (30 cm × 30 cm × 0.1mm) was used in this simulation. A 1 mm diameter pencil beam of 1 million incident carbon-ions was used in all simulations presented. The incident energies per nucleon of the carbon beams studied were selected 155 MeV, 262 MeV and 369 MeV. The energy deposition, total kinetic energy, fluence, and dose averaged LET of each secondary particle produced within each detection sheet was determined to study their variations with depth. The particles investigated were gamma, neutron, electron, positron, proton, deuteron, triton, alpha, He- 3, Li-6, Li-7, Be-7, Be-9, Be-10, B-10, B-1 1, C-1 1, C-12, C-13, C-14, N-13, N-14, N-15, O-16. The relative dose contributions of four secondary ions (B-11, C-1 1, Alpha and Proton) were found to be each greater than 1%. The highest dose averaged LET value was from N-13, though its averaged dose contribution was less than 5×10-4 %. The secondary particles contribute small portion to the total dose deposited from primary carbon beam. Though heavier ions (N, O) show significant higher LET values, their relative dose contributions were negligible.


cis-Conformation of indigo in the coordination complex (indigo-O,O)(Cp*CrIICl).
The interaction of decamethylchromocene (Cp*2Cr) with indigo in the presence of a Cl- source yields the coordination complex (indigo-O,O)(Cp*CrIICl) (1) in which one Cp* ligand at chromium is substituted by indigo. Indigo adopts an unusual cis-conformation in 1, allowing the coordination of both indigo carbonyl groups to one CrII center. Complex 1 contains CrII with an S = 1 spin state and indigo0. At the same time, calculations show that an excited ionic state is positioned close to the neutral ground state, providing the appearance of intense low-energy NIR bands in the spectrum of 1 at 820 and 1002 nm attributed to metal-to-ligand charge transfer.


Relationship between the size of patency file and apical extrusion of sodium hypochlorite.
Sodium hypochlorite (NaOCl) is the most widely used endodontic irrigant because of its excellent antimicrobial, organic tissue dissolving, and lubricating properties. However, it is highly cytotoxic to the periapical tissues. This study evaluated in vitro the extrusion of 5.25% NaOCl through the apical foramina of mesiobuccal (MB) root canals of maxillary first molars in two experimental conditions: Before apical debridement and after apical debridement with different instrument sizes to ensure direct access to the apical foramen (apical patency). Coronal accesses were prepared in 17 teeth and the apical foramina of the distobuccal and palatal root canals were sealed. The teeth were held in acrylic receptacles with the roots turned upwards to reproduce their position in the maxillary dental arch. The receptacles were filled with a starch/KI solution (a reagent that changes its color to blue after contacting NaOCl) covering the roots. The experiment had two phases: P1: Irrigation of the MB canals with 5.25% NaOCl without previous establishment of apical patency; P2: Canal irrigation after use of size 10 K-file and size 15 Flexofile as patency files. Only specimens with no NaOCl extrusion in P1 were assigned to P2. NaOCl was delivered pressureless at the canal entrance. The moment that the starch/KI solution contacted NaOCl was captured on digital photographs. There was no NaOCl extrusion in nine specimens in P1, but all of these teeth had irrigant extrusion in P2. The 5.25% NaOCl used as an endodontic irrigant showed great capacity to extrude beyond both intact and small-sized apical foramina of MB root canals of maxillary first molars.


Suppression of ganglioside GD3 expression in a rat F-11 tumor cell line reduces tumor growth, angiogenesis, and vascular endothelial growth factor production.
Ganglioside GD3 is overexpressed in many types of tumors and may be associated with tumor progression and the development of metastatic potential. In our previous study (G. Zeng et al., Biochemistry, 38: 8762-8769, 1999), we established a subclone of the rat dorsal root ganglion-derived F-11 cells in which the expression of ganglioside GD3 was inhibited by stable transfection of the antisense vector against CMP-NeuAc: GM3 alpha2-8 sialyltransferase (GD3-synthase) gene. This cell line exhibits markedly reduced rate of tumor growth in vivo. Here, we further characterized the antisense-transfected cell line, and the results showed that these cells formed small, minimally vascularized tumors exhibiting extensive necrosis. In vivo Matrigel assay revealed reduced vascularization and low hemoglobin content in the antisense xenografts. Significantly fewer new vessels were found on the antisense xenografts and the skin around them than those on/around the xenografts formed by the sense-transfected and untransfected F-11 cells. The hemoglobin content of the antisense xenografts was much lower than that of the xenografts formed by the control cells. The reduced angiogenesis in the antisense xenografts was correlated with a decrease in vascular endothelial growth factor (VEGF) production. The expression of VEGF was suppressed in the antisense xenografts and the conditioned culture media of the antisense-transfected F-11 cells as determined by Western blotting analysis. This was further confirmed by immunohistochemistry of the tumors using antibodies against VEGF and platelet/endothelial cell adhesion molecule (PECAM-1). Therefore, our results demonstrate that reduced tumor growth in nude mice by suppression of GD3-synthase expression in F-11 cells results from minimal angiogenesis of the tumors through down-regulation of the VEGF expression, which indicates an important role for GD3 in tumor angiogenesis.


Impact of state-specific Medicaid reimbursement and eligibility policies on receipt of cancer screening.
Although state Medicaid programs cover cancer screening, Medicaid beneficiaries are less likely to be screened for cancer and are more likely to present with tumors of an advanced stage than are those with other insurance. The current study was performed to determine whether state Medicaid eligibility and reimbursement policies affect the receipt of breast, cervical, and colon cancer screening among Medicaid beneficiaries. Cross-sectional regression analyses of 2007 Medicaid data from 46 states and the District of Columbia were performed to examine associations between state-specific Medicaid reimbursement/eligibility policies and receipt of cancer screening. The study sample included individuals aged 21 years to 64 years who were enrolled in fee-for-service Medicaid for at least 4 months. Subsamples eligible for each screening test were: Papanicolaou test among 2,136,511 patients, mammography among 792,470 patients, colonoscopy among 769,729 patients, and fecal occult blood test among 753,868 patients. State-specific Medicaid variables included median screening test reimbursement, income/financial asset eligibility requirements, physician copayments, and frequency of eligibility renewal. Increases in screening test reimbursement demonstrated mixed associations (positive and negative) with the likelihood of receiving screening tests among Medicaid beneficiaries. In contrast, increased reimbursements for office visits were found to be positively associated with the odds of receiving all screening tests examined, including colonoscopy (odds ratio [OR], 1.07; 95% confidence interval [95% CI], 1.06-1.08), fecal occult blood test (OR, 1.09; 95% CI, 1.08-1.10), Papanicolaou test (OR, 1.02; 95% CI, 1.02-1.03), and mammography (OR, 1.02; 95% CI, 1.02-1.03). Effects of other state-specific Medicaid policies varied across the screening tests examined. Increased reimbursement for office visits was consistently associated with an increased likelihood of being screened for cancer, and may be an important policy tool for increasing screening among this vulnerable population.


Correction of thermal artifacts in plethysmographic airway resistance measurements.
Specific airway resistance (sRaw) measured by body plethysmography without conditioning of the inspired air to BTPS exhibits a strong frequency dependence related to the fact that the warming and wetting of the gas in the airways is not instantaneous (R. Peslin, C. Duvivier, M. Vassiliou, and C. Gallina. J. Appl. Physiol. 79: 1958-1965, 1995). We have tested three methods in 21 healthy subjects to correct for that artifact by using a simple model, assuming a first-order thermal process characterized by a single time constant. The corrections required entering an assumed constant value for (methods 1 and 2) and/or for airway inertance (methods 1 and 3) and/or measuring the inspired gas temperature and water vapor saturation (methods 2 and 3). The frequency dependence of sRaw was measured from 0.5 to 3 Hz both with (sRawETPS) and without (sRawam) gas conditioning. With optimal values for and/or airway inertance, the mean difference between sRawam and sRawETPS was close to zero with all three methods, but the root mean square difference was significantly lower with method 2 (0.83 +/- 0.35 hPa.s compared with 1.21 +/- 0.54 and 1.20 +/- 0.49 hPa.s with methods 1 and 2, respectively). We conclude that the thermal artifact of sRaw measurements may be best corrected by using temperature measurements and an assumed time constant (0.152 s with our equipment).


Hot spot detection and spatio-temporal dispersion of dengue fever in Hanoi, Vietnam.
Dengue fever (DF) in Vietnam remains a serious emerging arboviral disease, which generates significant concerns among international health authorities. Incidence rates of DF have increased significantly during the last few years in many provinces and cities, especially Hanoi. The purpose of this study was to detect DF hot spots and identify the disease dynamics dispersion of DF over the period between 2004 and 2009 in Hanoi, Vietnam. Daily data on DF cases and population data for each postcode area of Hanoi between January 1998 and December 2009 were obtained from the Hanoi Center for Preventive Health and the General Statistic Office of Vietnam. Moran's I statistic was used to assess the spatial autocorrelation of reported DF. Spatial scan statistics and logistic regression were used to identify space-time clusters and dispersion of DF. The study revealed a clear trend of geographic expansion of DF transmission in Hanoi through the study periods (OR 1.17, 95% CI 1.02-1.34). The spatial scan statistics showed that 6/14 (42.9%) districts in Hanoi had significant cluster patterns, which lasted 29 days and were limited to a radius of 1,000 m. The study also demonstrated that most DF cases occurred between June and November, during which the rainfall and temperatures are highest. There is evidence for the existence of statistically significant clusters of DF in Hanoi, and that the geographical distribution of DF has expanded over recent years. This finding provides a foundation for further investigation into the social and environmental factors responsible for changing disease patterns, and provides data to inform program planning for DF control.


Neuroinflammation and endoplasmic reticulum stress are coregulated by crocin to prevent demyelination and neurodegeneration.
Endoplasmic reticulum (ER) stress is a homeostatic mechanism, which is used by cells to adapt to intercellular and intracellular changes. Moreover, ER stress is closely linked to inflammatory pathways. We hypothesized that ER stress is an integral component of neuroinflammation and contributes to the development of neurological diseases. In autopsied brain specimens from multiple sclerosis (MS) and non-MS patients, XBP-1 spliced variant (XBP-1/s) was increased in MS brains (p < 0.05) and was correlated with the expression of the human endogenous retrovirus-W envelope transcript, which encodes the glycoprotein, Syncytin-1 (p < 0.05). In primary human fetal astrocytes transfected with a Syncytin-1-expressing plasmid, XBP-1/s, BiP, and NOS2 were induced, which was suppressed by crocin treatment (p < 0.05). Crocin also protected oligodendrocytes exposed to cytotoxic supernatants derived from Syncytin-1-expressing astrocytes (p < 0.05) and NO-mediated oligodendrocytotoxicity (p < 0.05). During experimental autoimmune encephalomyelitis (EAE), the transcript levels of the ER stress genes XBP-1/s, BiP, PERK, and CHOP were increased in diseased spinal cords compared with healthy littermates (p < 0.05), although CHOP expression was not involved in the EAE disease phenotype. Daily treatment with crocin starting on day 7 post-EAE induction suppressed ER stress and inflammatory gene expression in spinal cords (p < 0.05), which was accompanied by preserved myelination and axonal density, together with reduced T cell infiltration and macrophage activation. EAE-associated neurobehavioral deficits were also ameliorated by crocin treatment (p < 0.05). These findings underscored the convergent roles of pathogenic ER stress and immune pathways in neuroinflammatory disease and point to potential therapeutic applications for crocin.


Long-term treatment with carprofen of 805 dogs with osteoarthritis.
The pain-relieving effect of carprofen and tolerance to the drug were investigated in 805 dogs that were lame as a result of osteoarthritis. The dogs were of different breeds, ages and bodyweights and of both sexes, and were selected from 51 veterinary clinics. Each dog was treated orally by its owner with 4 mg/kg carprofen for 84 consecutive days. Twenty-four dogs were removed from the study because of side effects, and 55 left the study for reasons unrelated to the treatment. The condition of the dogs and the benefit of the treatment were evaluated by the veterinary surgeons and the owners after 14 days, and at the end of the period of treatment, when 194 of the dogs (26.7 per cent) were no longer lame, and 357 (49.2 per cent) had improved. The period for which the dogs had been lame before entering the study significantly (P<0.01) affected the results and the rate of improvement. Too much exercise during the 84 days of treatment caused some dogs to relapse.


Virtual conversion from metal object to dielectric object using metamaterials.
We propose an illusion device which transforms a perfectly-electric-conducting (PEC) object into a virtual dielectric object with arbitrary material parameters. Such an illusion device has unconventional electromagnetic properties as verified by accurate numerical simulations. The presented illusion device is composed of inhomogeneous and anisotropic media with finite and positive permittivity and permeability components. Hence the designed device is possible to be realized using artificial metamaterials.