Remote sensing of aerosols in the Arctic for an evaluation of global climate model simulations.
In this study Moderate Resolution Imaging Spectroradiometer (MODIS) Aqua retrievals of aerosol optical thickness (AOT) at 555 nm are compared to Sun photometer measurements from Svalbard for a period of 9 years. For the 642 daily coincident measurements that were obtained, MODIS AOT generally varies within the predicted uncertainty of the retrieval over ocean (ΔAOT = ±0.03 ± 0.05 · AOT). The results from the remote sensing have been used to examine the accuracy in estimates of aerosol optical properties in the Arctic, generated by global climate models and from in situ measurements at the Zeppelin station, Svalbard. AOT simulated with the Norwegian Earth System Model/Community Atmosphere Model version 4 Oslo global climate model does not reproduce the observed seasonal variability of the Arctic aerosol. The model overestimates clear-sky AOT by nearly a factor of 2 for the background summer season, while tending to underestimate the values in the spring season. Furthermore, large differences in all-sky AOT of up to 1 order of magnitude are found for the Coupled Model Intercomparison Project phase 5 model ensemble for the spring and summer seasons. Large differences between satellite/ground-based remote sensing of AOT and AOT estimated from dry and humidified scattering coefficients are found for the subarctic marine boundary layer in summer. Remote sensing of AOT is very useful in validation of climate models.


Coupling coherence distinguishes structure sensitivity in protein electron transfer.
Quantum mechanical analysis of electron tunneling in nine thermally fluctuating cytochrome b562 derivatives reveals two distinct protein-mediated coupling limits. A structure-insensitive regime arises for redox partners coupled through dynamically averaged multiple-coupling pathways (in seven of the nine derivatives) where heme-edge coupling leads to the multiple-pathway regime. A structure-dependent limit governs redox partners coupled through a dominant pathway (in two of the nine derivatives) where axial-ligand coupling generates the single-pathway limit and slower rates. This two-regime paradigm provides a unified description of electron transfer rates in 26 ruthenium-modified heme and blue-copper proteins, as well as in numerous photosynthetic proteins.


Failure of transient lower oesophageal sphincter relaxation in response to gastric distension in patients with achalasia: evidence for neural mediation of transient lower oesophageal sphincter relaxations.
Transient lower oesophageal sphincter relaxation (LOSR) is the major mechanism underlying gastro-oesophageal reflux. The mediation and control of LOSRs are incompletely understood but evidence suggests a neural inhibitory mechanism. In this study we have evaluated the effect of gastric distension on LOS function in 16 patients with untreated idiopathic achalasia and compared it with that in 10 healthy controls. With the subjects sitting, the stomach was distended with a liquid mixture that generated 750 ml CO2. Oesophageal pH and motility were monitored for 10 minutes before and after distension. In normal controls, gastric distension induced a four-fold increase in the rate of LOSRs and gas reflux episodes (as evidenced by oesophageal common cavities), whereas this response was absent in the achalasia patients. Basal LOS pressure did not change in either group. These findings are consistent with the notion that transient LOSRs induced by gastric distension are neurally mediated, probably by the same inhibitory nerves that govern swallow mediated LOS relaxation.


NPC1L1 haplotype is associated with inter-individual variation in plasma low-density lipoprotein response to ezetimibe.
NPC1L1 encodes a putative intestinal sterol transporter which is the likely target for ezetimibe, a new type of lipid-lowering medication. We previously reported rare non-synonymous mutations in NPC1L1 in an individual who had no plasma lipoprotein response to ezetimibe. We next hypothesized that common variants in NPC1L1 would underlie less extreme inter-individual variations in the plasma LDL cholesterol response to ezetimibe. In 101 dyslipidemic subjects, we found that NPC1L1 haplotype was significantly associated with inter-individual variation in the response of plasma LDL cholesterol to treatment with ezetimibe for 12 weeks. Specifically, about one subject in eight lacked the common NPC1L1 haplotype 1735C-25342A-27677T and these subjects had a significantly greater reduction in plasma LDL cholesterol with ezetimibe than subjects with at least one copy of this haplotype (-35.9+4.0 versus -23.6+1.6 percent reduction, P = 0.0054). This was paralleled by a similar non-significant trend of between-haplotype difference in reduction of total cholesterol. These preliminary pharmacogenetic results suggest that NPC1L1 variation is associated with inter-individual variation in response to ezetimibe treatment.


What is optimized in convex relaxations for multilabel problems: connecting discrete and continuously inspired MAP inference.
In this work, we present a unified view on Markov random fields (MRFs) and recently proposed continuous tight convex relaxations for multilabel assignment in the image plane. These relaxations are far less biased toward the grid geometry than Markov random fields on grids. It turns out that the continuous methods are nonlinear extensions of the well-established local polytope MRF relaxation. In view of this result, a better understanding of these tight convex relaxations in the discrete setting is obtained. Further, a wider range of optimization methods is now applicable to find a minimizer of the tight formulation. We propose two methods to improve the efficiency of minimization. One uses a weaker, but more efficient continuously inspired approach as initialization and gradually refines the energy where it is necessary. The other one reformulates the dual energy enabling smooth approximations to be used for efficient optimization. We demonstrate the utility of our proposed minimization schemes in numerical experiments. Finally, we generalize the underlying energy formulation from isotropic metric smoothness costs to arbitrary nonmetric and orientation dependent smoothness terms.


Deep roots for mid-ocean-ridge volcanoes revealed by plagioclase-hosted melt inclusions.
The global mid-ocean ridge system is the most extensive magmatic system on our planet and is the site of 75 per cent of Earth's volcanism1. The vertical extent of mid-ocean-ridge magmatic systems has been considered to be restricted: even at the ultraslow-spreading Gakkel mid-ocean ridge under the Arctic Ocean, where the lithosphere is thickest, crystallization depths of magmas that feed eruptions are thought to be less than nine kilometres2. These depths were determined using the volatile-element contents of melt inclusions, which are small volumes of magma that become trapped within crystallizing minerals. In studies of basaltic magmatic systems, olivine is the mineral of choice for this approach2-6. However, pressures derived from olivine-hosted melt inclusions are at odds with pressures derived from basalt major-element barometers7 and geophysical measurements of lithospheric thickness8. Here we present a comparative study of olivine- and plagioclase-hosted melt inclusions from the Gakkel mid-ocean ridge. We show that the volatile contents of plagioclase-hosted melt inclusions correspond to much higher crystallization pressures (with a mean value of 270 megapascals) than olivine-hosted melt inclusions (with a mean value of 145 megapascals). The highest recorded pressure that we find equates to a depth 16.4 kilometres below the seafloor. Such higher depths are consistent with both the thickness of the Gakkel mid-ocean ridge lithosphere and with pressures reconstructed from glass compositions. In contrast to previous studies using olivine-hosted melt inclusions, our results demonstrate that mid-ocean-ridge volcanoes may have magmatic roots deep in the lithospheric mantle, at least at ultraslow-spreading ridges.


Green synthesis of Fe3O4 nanoparticles with controlled morphologies using urease and their application in dye adsorption.
This paper describes a simple and environmentally friendly method for the preparation of highly stable dispersions of Fe3O4 nanoparticles with controlled morphologies, in the same synthesis system for the first time. During the process, the Fe3O4 nanoparticles are formed using urease as a multifunctional reagent, including catalyst, template and dispersant, due to its enzymatic activity and special enzymatic steric structure. A possible formation mechanism for these Fe3O4 nanoparticles, which have various morphologies including nanospheres, nanosheets and nanorods, is proposed. The as-prepared nanoparticles show a larger specific surface area and a stronger magnetism, which enhances their dye adsorption capacity and increases their potential for application in wastewater treatment.


Smoking patterns of Asian-American youth in California and their relationship with acculturation.
To examine patterns of smoking behavior among subgroups of Asian-American youth in California and their relationship with acculturation status. Data were from the 1990-1996 California Tobacco Survey and the California Youth Tobacco Survey, which assessed smoking-related attitudes and behaviors among California youth in grades 7-12. Among the 20,482 respondents, 1,810 were Asian-Americans. Variables assessed included lifetime smoking prevalence, 30-day smoking prevalence, and age of smoking onset. Acculturation status was assessed with measures of English usage, language spoken at home, and age at immigration to the United States. Of the 1,810 Asian-Americans (52% male), 19% were Chinese, 33% Filipino, 8% Japanese, 13% Korean, and 26% other Asian-Americans. Lifetime smoking prevalence was 16.1% for Asians and 26.1% for non-Asians. The 30-day smoking rate was 6.9% for Asians and 14.2% for non-Asians. Subgroup-specific analyses revealed differences in lifetime smoking prevalence (18.9% for Filipinos, 17.3% for Japanese, 16.3 % for Koreans, 11.0% for Chinese, and 13.7% for other Asian-Americans) and 30-day smoking rate (8.6% for Filipinos, 8.3% for Koreans, 7.4% for Japanese, 2.8% for Chinese, and 7.2% for other Asian-Americans). Gender differences in lifetime smoking prevalence varied by Asian subgroup; smoking prevalence was higher among males than among females for Chinese and Koreans, but smoking prevalence was higher among females than among males for Japanese and other Asians. The average age of smoking onset was 12.9 years for Asians and 12.8 years for non-Asians. Age of smoking onset differed among Asian-American subgroups but did not differ by gender. In addition, smoking behaviors of the Asian respondents were significantly associated with their acculturation status. Asian-American youth have relatively lower smoking rates and later age of smoking onset than non-Asian youth in California. In addition, subgroups of Asian-American youth vary widely in their smoking behavior. High levels of acculturation among Asian-American youth are associated with higher smoking prevalence rates and earlier age of smoking onset.


Comparative Study of Different Methods for the Prediction of Drug-Polymer Solubility.
In this study, a comparison of different methods to predict drug-polymer solubility was carried out on binary systems consisting of five model drugs (paracetamol, chloramphenicol, celecoxib, indomethacin, and felodipine) and polyvinylpyrrolidone/vinyl acetate copolymers (PVP/VA) of different monomer weight ratios. The drug-polymer solubility at 25 °C was predicted using the Flory-Huggins model, from data obtained at elevated temperature using thermal analysis methods based on the recrystallization of a supersaturated amorphous solid dispersion and two variations of the melting point depression method. These predictions were compared with the solubility in the low molecular weight liquid analogues of the PVP/VA copolymer (N-vinylpyrrolidone and vinyl acetate). The predicted solubilities at 25 °C varied considerably depending on the method used. However, the three thermal analysis methods ranked the predicted solubilities in the same order, except for the felodipine-PVP system. Furthermore, the magnitude of the predicted solubilities from the recrystallization method and melting point depression method correlated well with the estimates based on the solubility in the liquid analogues, which suggests that this method can be used as an initial screening tool if a liquid analogue is available. The learnings of this important comparative study provided general guidance for the selection of the most suitable method(s) for the screening of drug-polymer solubility.


Maximal shuttle running over 40 m as a measure of anaerobic performance.
Over the last decade increasing interest has been shown in the measurement of anaerobic power and capacity in athletic men. These physiological characteristics have been determined predominantly using cycle ergometry and treadmill sprinting. The purpose of the present study was to examine the relationship between 40-m maximal shuttle run times and performance indices obtained during treadmill sprinting and cycle ergometry. Moderate correlations were found between 10-m split times (the time taken to cover the initial 10 m of the shuttle course) and treadmill peak power outputs (r = -0.67; P < 0.05). Similar relationships were also found between the fastest 40-m time and mean power outputs generated on both the treadmill and cycle ergometer (r = -0.67; P < 0.05) and (r = -0.75; P < 0.05) respectively. The correlations remained unchanged when the values were adjusted for body weight (W kg-1). The results of the present study suggest that maximal 40-m shuttle running ability may reflect anaerobic indices of power and capacity, determined using standard laboratory procedures.


Hepatocarcinogenicity of chloral hydrate, 2-chloroacetaldehyde, and dichloroacetic acid in the male B6C3F1 mouse.
The chlorinated acetaldehydes, chloral hydrate (CH) and 2-chloroacetaldehyde (CAA), have been identified as chlorination by-products in finished drinking water supplies. Although both chemicals are genotoxic, their potential for carcinogenicity had not been adequately explored. The studies reported here are chronic bioassays conducted with male B6C3F1 mice exposed to levels of 1 g/liter CH and 0.1 g/liter CAA via the drinking water for 104 weeks. Distilled water (H2O) served as the untreated control and dichloroacetic acid (DCA; 0.5 g/liter), another chlorine disinfection by-product, was included. The mean daily ingested doses were approximately 166 mg/kg/day for CH, 17 mg/kg/day for CAA, and 93 mg/kg/day for DCA. Evaluations included mortality, body weight, organ weights, gross pathology, and histopathology. The primary target organ was the liver as the organ weights and pathological changes in the other organs (spleen, kidneys, and testes) were comparable between the treated groups and the H2O control group. Liver weights were increased for all three test chemicals at the terminal euthanasia with the greatest increase seen in the CH and DCA groups. Hepatocellular necrosis was induced by all three test chemicals, and it was also most prevalent and severe in the CH and DCA groups. A significant increase in the prevalence of liver tumors was seen for all three chemicals. The strongest response was with DCA, in which 63% of the 104-week survivors had hepatocellular carcinomas (carcinomas) and 42% possessed hepatocellular adenomas (adenomas) and the combined prevalence for carcinomas plus adenoma was 75%. The corresponding prevalence rate for carcinomas, adenomas, and combined tumors were 46, 29, and 71%; 31, 8, and 38%; and 10, 5, and 15% for CH, CAA, and H2O, respectively. In addition to the tumors we evaluated the prevalence of a possible preneoplastic lesion, the hepatocellular hyperplastic nodule (nodules), a lesion which occurred in all three treated groups but not in the H2O group.


Culture as common sense: perceived consensus versus personal beliefs as mechanisms of cultural influence.
The authors propose that culture affects people through their perceptions of what is consensually believed. Whereas past research has examined whether cultural differences in social judgment are mediated by differences in individuals' personal values and beliefs, this article investigates whether they are mediated by differences in individuals' perceptions of the views of people around them. The authors propose that individuals who perceive that traditional views are culturally consensual (e.g., Chinese participants who believe that most of their fellows hold collectivistic values) will themselves behave and think in culturally typical ways. Four studies of previously well-established cultural differences found that cultural differences were mediated by participants' perceived consensus as much as by participants' personal views. This held true for cultural differences in the bases of compliance (Study 1), attributional foci (Study 2), and counterfactual thinking styles (Study 3). To tease apart the effect of consensus perception from other possibly associated individual differences, in Study 4, the authors experimentally manipulated which of 2 cultures was salient to bicultural participants and found that judgments were guided by participants' perception of the consensual view of the salient culture.


Biochemical Screening for Pulmonary Hypertension in Preterm Infants with Bronchopulmonary Dysplasia.
Pulmonary hypertension (PH) in infants with bronchopulmonary dysplasia (BPD) is associated with increased morbidity and mortality. Elevated levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and decreased levels of amino acid precursors of nitric oxide (NO) have been associated with PH, but have not been studied in infants with PH secondary to BPD. The aim of this study was to identify a biochemical marker for PH in infants with BPD. Twenty infants, born at <27 weeks' gestational age (GA) and/or with a birth weight (BW) ≤750 g, who met the criteria for BPD at 36 weeks' corrected GA (CGA) were enrolled in this cross-sectional pilot study. A screening echocardiogram was conducted at 36-38 weeks' CGA and plasma NT-proBNP and amino acid levels were obtained within 1 week of the screening echocardiogram. Five infants (25%) had echocardiographic evidence of PH. GA and BW were not significantly different between the 2 groups (a PH group and a No PH group). NT-proBNP was significantly elevated in the PH group (median 1,650 vs. 520 pg/ml; p = 0.001) but citrulline levels were significantly lower (median 21 vs. 36 μmol/l; p = 0.005). Arginine levels were not significantly different between the groups (median 78 vs. 79 μmol/l; p = 1). NT-proBNP and the NO precursor citrulline may be cost-effective biochemical markers for screening for the presence of PH in preterm infants who have BPD. If validated in a larger study, such biochemical markers may, in part, replace PH screening echocardiograms in these patients.


Role for glyoxalase I in Alzheimer's disease.
P301L mutant tau transgenic mice develop neurofibrillary tangles, a histopathologic hallmark of Alzheimer's disease and frontotemporal dementia (FTDP-17). To identify differentially expressed genes and to gain insight into pathogenic mechanisms, we performed a stringent analysis of the microarray dataset obtained with RNA from whole brains of P301L mutant mice and identified a single up-regulated gene, glyoxalase I. This enzyme plays a critical role in the detoxification of dicarbonyl compounds and thereby reduces the formation of advanced glycation end products. In situ hybridization analysis revealed expression of glyoxalase I in all brain areas analyzed, both in transgenic and control mice. However, levels of glyoxalase I protein were significantly elevated in P301L brains, as shown by Western blot analysis and immunohistochemistry. Moreover, a glyoxalase I-specific antiserum revealed many intensely stained flame-shaped neurons in Alzheimer's disease brain compared with brains from nondemented controls. In addition, we examined a single nucleotide polymorphism predicting a nonconservative amino acid substitution at position 111 (E111A) in ethnically independent populations. We identified significant and consistent deviations from Hardy-Weinberg equilibrium, which points to the presence of selection forces. The E111A single nucleotide polymorphism was not associated with the risk for Alzheimer's disease in the overall population. Together, our data demonstrate the potential of transcriptomics applied to animal models of human diseases. They suggest a previously unidentified role for glyoxalase I in neurodegenerative disease.


High power and widely tunable Si hybrid external-cavity laser for power efficient Si photonics WDM links.
A highly efficient silicon (Si) hybrid external cavity laser with a wavelength tunable ring reflector is fabricated on a complementary metal-oxide semiconductor (CMOS)-compatible Si-on-insulator (SOI) platform and experimental results with high output power are demonstrated. A III-V semiconductor gain chip is edge-coupled into a SOI cavity chip through a SiN(x) spot size converter and Si grating couplers are incorporated to enable wafer-scale characterization. The laser output power reaches 20 mW and the highest wall-plug efficiency of 7.8% is measured at 17.3 mW in un-cooled condition. The laser wavelength tuning ranges are 8 nm for the single ring reflector cavity and 35 nm for the vernier ring reflector cavity, respectively. The Si hybrid laser is a promising light source for energy-efficient Si CMOS photonic links.


Strategy Training Shows Promise for Addressing Disability in the First 6 Months After Stroke.
Cognitive impairments occur frequently after stroke and contribute to significant disability. Strategy training shows promise but has not been examined in the acute phase of recovery. We conducted a single-blind randomized pilot study estimating the effect of strategy training, relative to reflective listening (attention control), for reducing disability and executive cognitive impairments. Thirty participants with acute stroke who were enrolled in inpatient rehabilitation and had cognitive impairments were randomized to receive strategy training (n = 15, 10 sessions as adjunct to usual inpatient rehabilitation) or reflective listening (n = 15, same dose). The Functional Independence Measure assessed disability at baseline, rehabilitation discharge, 3, and 6 months. The Color Word Interference Test of the Delis-Kaplan Executive Function System assessed selected executive cognitive impairments (inhibition, flexibility) at baseline, 3, and 6 months. Changes in Functional Independence Measure scores for the 2 groups over 6 months showed significant effects of group (F1,27 = 9.25, P = .005), time (F3,74 = 96.00, P < .001), and group * time interactions (F3,74 = 4.37, P < .007) after controlling for baseline differences in stroke severity (F1,27 = 6.74, P = .015). Color Word Interference Inhibition scores showed significant effects of group (F1,26 = 6.50, P = .017) and time (F2,34 = 4.74, P = .015), but the group * time interaction was not significant (F2,34 = 2.55, P = .093). Color Word Interference Cognitive Flexibility scores showed significant effects of group (F1,26 = 23.41, P < .001), time (F2,34 = 12.77, P < .001), and group * time interactions (F2,34 = 7.83, P < .002). Interaction effects suggested greater improvements were associated with strategy training. Strategy training shows promise for addressing disability in the first 6 months after stroke. Lessons from this pilot study may inform future clinical trials.


Vitamin D insufficiency in older female community-dwelling acute hospital admissions and the response to supplementation.
A significant proportion of the older population may exhibit vitamin D insufficiency. We sought to establish the proportion of 25-hydroxyvitamin D (25OHD) insufficient individuals in an older female cohort presenting for acute medical admission and how they responded to supplementation. A prospective cohort study. Hospital admissions followed up as a population-based study. A total of 114 consecutive female acute medical admissions aged over 65 years from November 2003 to January 2004 were enrolled. All admissions with hypercalcaemia, metabolic bone disease (other than osteoporosis/osteomalacia) and creatinine > 150 micromol/l were excluded. iPTH, calcium and 25OHD levels were measured in each patient. Of the total, 22 were already receiving calcium and vitamin D supplementation at enrolment. The remaining 92 were commenced on 800 IU of vitamin D and 1 g calcium, and levels were reassessed after supplementation for 3 months. 25-Hydroxyvitamin D insufficiency, as defined by a 25OHD concentration of < 50 nmol/l, was present in 86 (75.4%) patients at initial assessment (mean 35.8 nmol/l, s.d. 23.3). Secondary hyperparathyroidism was present in only 36.7% of those with 25OHD deficiency at baseline. Of the total, 51 (44.7%) patients presented for follow-up. 25-Hydroxyvitamin D concentration increased in this group from 42.1 nmol/l (s.d. 26.6) to 59.5 nmol/l (s.d. 27.4) after supplementation, P < 0.001, but 18(35.3%) still remained deficient. There was no significant change in iPTH or calcium following supplementation. Assessment of compliance revealed 6 (11.7%) admitted to partial or non-compliance. Insufficiency of 25OHD was very common in this cohort. Despite calcium and vitamin D supplementation, 25OHD concentrations failed to reach normality in a significant proportion. Maintaining vitamin D and calcium intake at the level of current recommended doses may not be sufficient to ensure adequate 25OHD stores.


The relationship between encephalitis lethargica and influenza: a critical analysis.
Since encephalitis lethargica's (EL) prevalence in the 1920s, epidemiologic and clinical debate has persisted over whether EL was caused by, potentiated by, or merely coincident with the Spanish influenza pandemic. Epidemiologic analyses generally suggest that the disorders were coincidental. Beginning in the 1970s, modern experiments on archival brain samples mainly failed to confirm a direct relationship between influenza and EL. These experimental studies have technical limitations, e.g., the appropriateness of antibodies, polymerase chain reaction (PCR) primers and controls, and the extreme paucity and age of available material. These factors render the case against influenza less decisive than currently perceived. Nevertheless, there is little direct evidence supporting influenza in the etiology of EL. Almost 100 years after the EL epidemic, its etiology remains enigmatic, raising the possibility of a recurrence of EL in a future influenza pandemic.


Acceptability of a theory-based sedentary behaviour reduction intervention for older adults ('On Your Feet to Earn Your Seat').
Adults aged 60 years and over spend most time sedentary and are the least physically active of all age groups. This early-phase study explored acceptability of a theory-based intervention to reduce sitting time and increase activity in older adults, as part of the intervention development process. An 8-week uncontrolled trial was run among two independent samples of UK adults aged 60-75 years. Sample 1, recruited from sheltered housing on the assumption that they were sedentary and insufficiently active, participated between December 2013 and March 2014. Sample 2, recruited through community and faith centres and a newsletter, on the basis of self-reported inactivity (<150 weekly minutes of moderate-to-vigorous activity) and sedentary behaviour (≥ 6 h mean daily sitting), participated between March and August 2014. Participants received a booklet offering 16 tips for displacing sitting with light-intensity activity and forming activity habits, and self-monitoring 'tick-sheets'. At baseline, 4-week, and 8-week follow-ups, quantitative measures were taken of physical activity, sedentary behaviour, and habit. At 8 weeks, tick-sheets were collected and a semi-structured interview conducted. Acceptability was assessed for each sample separately, through attrition and adherence to tips, ANOVAs for behaviour and habit changes, and, for both samples combined, thematic analysis of interviews. In Sample 1, 12 of 16 intervention recipients completed the study (25% attrition), mean adherence was 40% (per-tip range: 15-61%), and there were no clear patterns of changes in sedentary or physical activity behaviour or habit. In Sample 2, 23 of 27 intervention recipients completed (15% attrition), and mean adherence was 58% (per-tip range: 39-82%). Sample 2 decreased mean sitting time and sitting habit, and increased walking, moderate activity, and activity habit. Qualitative data indicated that both samples viewed the intervention positively, found the tips easy to follow, and reported health and wellbeing gains. Low attrition, moderate adherence, and favourability in both samples, and positive changes in Sample 2, indicate the intervention was acceptable. Higher attrition, lower adherence, and no apparent behavioural impact among Sample 1 could perhaps be attributable to seasonal influences. The intervention has been refined to address emergent acceptability problems. An exploratory controlled trial is underway.


Effect of ultrasound pre-treatment of hemp (Cannabis sativa L.) seed on supercritical CO2 extraction of oil.
Ultrasound pre-treatment of intact hemp seeds without any solvent assistance was carried out for 10, 20 and 40 min prior to SCCO2 extraction at 40 °C, 300 bar and 45 kg CO2/kg feed. Sonication time effect on SC-CO2 extraction was investigated by the extraction kinetics. The maximum extraction yield was estimated to be 24.03 (% w/w) after 10 min of ultrasonic pre-treatment. The fatty acid compositions of the oils extracted by SC-CO2 without and with ultrasound pre-treatments was analyzed using gas chromatography. It was shown that the content of linoleic, α-linolenic and oleic acids (the most abundant unsaturated fatty acids) of the hemp seed oils were not affected significantly by the application of ultrasound. UV spectroscopy indices (K232 and K268) and antiradical capacity were used to follow the quality of oils. Significant were the changes in their antiradical capacity due to ultrasound treatment. A comparison with the oil extracted by Soxhlet was also given.


Non-English speakers consulting with the GP in their own language: a cross-sectional survey.
The Patient Enablement Instrument (PEI) gives counterintuitive results with patients who normally speak non-English languages at home. The aim of this study was to find out more about why patients speaking languages other than English were more enabled in a shorter time than English-speaking patients. A cross-sectional consultation-based questionnaire survey was conducted of 2052 adult patients speaking languages other than English compared with 23790 English-speaking patients in four contrasting study areas in the UK Highest PEI scores in shortest consultation times were associated with South Asian language-speaking patients consulting in their own language. Multiple regression analysis showed that the language factors had an independent effect. We therefore conclude that these patients derive particular benefit from general practice consultations in their own language. Enablement may have a different meaning for patients speaking languages other than English.


Transcriptional regulatory functions of mammalian AP-endonuclease (APE1/Ref-1), an essential multifunctional protein.
The mammalian AP-endonuclease (APE1/Ref-1) plays a central role in the repair of oxidized and alkylated bases in mammalian genomes via the base excision repair (BER) pathway. However, APE1, unlike its E. coli prototype Xth, has two unique and apparently distinct transcriptional regulatory activities. APE1 functions as a redox effector factor (Ref-1) for several transcription factors including AP-1, HIF1-alpha, and p53. APE1 was also identified as a direct trans-acting factor for repressing human parathyroid hormone (PTH) and renin genes by binding to the negative calcium-response element (nCaRE) in their promoters. We have characterized APE1's post-translational modification, namely, acetylation which modulates its transcriptional regulatory function. Furthermore, stable interaction of APE1 with several other trans-acting factors including HIF-1alpha, STAT3, YB-1, HDAC1, and CBP/p300 and formation of distinct trans-acting complexes support APE1's direct regulatory function for diverse genes. Multiple functions of mammalian APE1, both in DNA repair and gene regulation, warrant extensive analysis of its own regulation and dissection of the mechanisms. In this review, we have discussed APE1's own regulation and its role as a transcriptional coactivator or corepressor by both redox-dependent and redox-independent (acetylation-mediated) mechanisms, and explore the potential utility of targeting these functions for enhancing drug sensitivity of cancer cells.


Guideline on the use of onabotulinumtoxinA in chronic migraine: a consensus statement from the European Headache Federation.
OnabotulinumtoxinA is being increasingly used in the management of chronic migraine (CM). Treatment with onabotulinumtoxinA poses challenges compared with traditional therapy with orally administered preventatives. The European Headache Federation identified an expert group that was asked to develop the present guideline to provide recommendations for the use of onabotulinumtoxinA in CM. The expert group recommend onabotulinumtoxinA as an effective and well-tolerated treatment of CM. Patients should preferably have tried two to three other migraine prophylactics before start of onabotulinumtoxinA. Patients with medication overuse should be withdrawn from the overused medication before initiation of onabotulinumtoxinA if feasible, if not onabotulinumtoxinA can be initiated from the start or before withdrawal. OnabotulinumtoxinA should be administered according to the PREEMPT injection protocol, i.e. injecting 155 U-195 U to 31-39 sites every 12-weeks. We recommend that patients are defined as non-responders, if they have less than 30% reduction in headache days per month during treatment with onabotulinumtoxinA. However other factors such as headache intensity, disability and patient preferences should also be considered when evaluating response. Treatment should be stopped, if the patient does not respond to the first two to three treatment cycles. Response to continued treatment with onabotulinumtoxinA should be evaluated by comparing the 4 weeks before with the 4 weeks after each treatment cycle. It is recommended that treatment is stopped in patients with a reduction to less than 10 headache days per month for 3 months and that patients are re-evaluated 4-5 months after stopping onabotulinumtoxinA to make sure that the patient has not returned to CM. Questions regarding efficacy and tolerability of onabotulinumtoxinA could be answered on the basis of scientific evidence. The other recommendations were mainly based on expert opinion. Future research on the treatment of CM with onabotulinumtoxinA may further improve the management of this highly disabling disorder.


Disseminate and recurrent infundibulo-folliculitis in an Indian patient: A case report with review of literature.
A 17-year-old male patient presented with multiple discrete and confluent monomorphic skin-colored pinhead-sized follicular papules, with occasional pustules distributed on the neck, upper chest, upper posterior trunk, and proximal extremities of 4 months duration. The lesions were asymptomatic, and there was no prior history of topical application or history of atopic dermatitis. Routine investigations were normal. Histopathology of the papules showed a mononuclear infiltrate at the infundibulum of the hair follicle. We made a final diagnosis of disseminate and recurrent infundibulo-folliculitis. The patient was started on NB-UVB and topical tacrolimus. We are reporting an interesting case in an Indian patient.


Dengue vaccine-induced CD8+ T cell immunity confers protection in the context of enhancing, interfering maternal antibodies.
Declining levels of maternal antibodies were shown to sensitize infants born to dengue-immune mothers to severe disease during primary infection, through the process of antibody-dependent enhancement of infection (ADE). With the recent approval for human use of Sanofi-Pasteur's chimeric dengue vaccine CYD-TDV and several vaccine candidates in clinical development, the scenario of infants born to vaccinated mothers has become a reality. This raises 2 questions: will declining levels of maternal vaccine-induced antibodies cause ADE; and, will maternal antibodies interfere with vaccination efficacy in the infant? To address these questions, the above scenario was modeled in mice. Type I IFN-deficient female mice were immunized with live attenuated DENV2 PDK53, the core component of the tetravalent DENVax candidate currently under clinical development. Pups born to PDK53-immunized dams acquired maternal antibodies that strongly neutralized parental strain 16681, but not the heterologous DENV2 strain D2Y98P-PP1, and instead caused ADE during primary infection with this strain. Furthermore, pups failed to seroconvert after PDK53 vaccination, owing to maternal antibody interference. However, a cross-protective multifunctional CD8+ T cell response did develop. Thus, our work advocates for the development of dengue vaccine candidates that induce protective CD8+ T cells despite the presence of enhancing, interfering maternal antibodies.


Molecular hints of two-step transition to convective flow via streamline percolation.
Convection is a key transport phenomenon important in many different areas, from hydrodynamics and ocean circulation to planetary atmospheres or stellar physics. However, its microscopic understanding still remains challenging. Here we numerically investigate the onset of convective flow in a compressible (non-Oberbeck-Boussinesq) hard disk fluid under a temperature gradient in a gravitational field. We uncover a surprising two-step transition scenario with two different critical temperatures. When the bottom plate temperature reaches a first threshold, convection kicks in (as shown by a structured velocity field) but gravity results in hindered heat transport as compared to the gravity-free case. It is at a second (higher) temperature that a percolation transition of advection zones connecting the hot and cold plates triggers efficient convective heat transport. Interestingly, this picture for the convection instability opens the door to unknown piecewise-continuous solutions to the Navier-Stokes equations.


IGF-I in human growth: lessons from defects in the GH-IGF-I axis.
The IGF system plays a critical role in all phases of human growth, including intrauterine, childhood and pubertal. The importance of IGF-I for both in utero as well as postnatal human growth is highlighted by rare human homozygous IGF1 mutations, which are characterized by intrauterine growth retardation (IUGR), microcephaly, mental retardation and severe postnatal growth failure. Clinical conditions of IGF-I resistance due to mutations in the IGF-I receptor (IGFIR) similarly lead to IUGR and postnatal growth retardation. Postnatal regulation of IGF-I production is predominantly GH dependent. Defects in the GH-IGF-I axis, including mutations in the GHR, STAT5B and IGFALS genes, lead to postnatal IGF deficiency and GH insensitivity. Patients are of normal birth size but present with severe postnatal growth failure, despite normal or elevated levels of GH. Other phenotypic features - immune deficiency for STAT5B defects and insulin insensitivity for IGFALS defects - are of note. Mutations identified have been predominantly recessive. The identification and assessment of genetic defects in the GH-IGF axis has greatly enhanced our understanding of the critical importance of IGF-I in human linear growth. Continued evaluations will facilitate better diagnosis and management of children presenting with abnormal growth and development.


Mediating Effect of Perceived Overweight on the Association between Actual Obesity and Intention for Weight Control; Role of Race, Ethnicity, and Gender.
Although obesity is expected to be associated with intention to reduce weight, this effect may be through perceived overweight. This study tested if perceived overweight mediates the association between actual obesity and intention to control weight in groups based on the intersection of race and gender. For this purpose, we compared Non-Hispanic White men, Non-Hispanic White women, African American men, African American women, Caribbean Black men, and Caribbean Black women. National Survey of American Life, 2001-2003 included 5,810 American adults (3516 African Americans, 1415 Caribbean Blacks, and 879 Non-Hispanic Whites). Weight control intention was entered as the main outcome. In the first step, we fitted race/gender specific logistic regression models with the intention for weight control as outcome, body mass index as predictor and sociodemographics as covariates. In the next step, to test mediation, we added perceived weight to the model. Obesity was positively associated with intention for weight control among all race × gender groups. Perceived overweight fully mediated the association between actual obesity and intention for weight control among Non-Hispanic White women, African American men, and Caribbean Black men. The mediation was only partial for Non-Hispanic White men, African American women, and Caribbean Black women. The complex relation between actual weight, perceived weight, and weight control intentions depends on the intersection of race and gender. Perceived overweight plays a more salient role for Non-Hispanic White women and Black men than White men and Black women. Weight loss programs may benefit from being tailored based on race and gender. This finding also sheds more light to the disproportionately high rate of obesity among Black women in US.


Plasmodium falciparum Blood Stage Antimalarial Vaccines: An Analysis of Ongoing Clinical Trials and New Perspectives Related to Synthetic Vaccines.
Plasmodium falciparum malaria is a disease causing high morbidity and mortality rates worldwide, mainly in sub-Saharan Africa. Candidates have been identified for vaccines targeting the parasite's blood stage; this stage is important in the development of symptoms and clinical complications. However, no vaccine that can directly affect morbidity and mortality rates is currently available. This review analyzes the formulation, methodological design, and results of active clinical trials for merozoite-stage vaccines, regarding their safety profile, immunological response (phase Ia/Ib), and protective efficacy levels (phase II). Most vaccine candidates are in phase I trials and have had an acceptable safety profile. GMZ2 has made the greatest progress in clinical trials; its efficacy has been 14% in children aged less than 5 years in a phase IIb trial. Most of the available candidates that have shown strong immunogenicity and that have been tested for their protective efficacy have provided good results when challenged with a homologous parasite strain; however, their efficacy has dropped when they have been exposed to a heterologous strain. In view of these vaccines' unpromising results, an alternative approach for selecting new candidates is needed; such line of work should be focused on how to increase an immune response induced against the highly conserved (i.e., common to all strains), functionally relevant, protein regions that the parasite uses to invade target cells. Despite binding regions tending to be conserved, they are usually poorly antigenic and/or immunogenic, being frequently discarded as vaccine candidates when the conventional immunological approach is followed. The Fundación Instituto de Inmunología de Colombia (FIDIC) has developed a logical and rational methodology based on including conserved high-activity binding peptides (cHABPs) from the main P. falciparum biologically functional proteins involved in red blood cell (RBC) invasion. Once appropriately modified (mHABPs), these minimal, subunit-based, chemically synthesized peptides can be used in a system covering the human immune system's main genetic variables (the human leukocyte antigen HLA-DR isotype) inducing a suitable, immunogenic, and protective immune response in most of the world's populations.


Modeling transport and deposition of contaminants to ecosystems of concern: a case study for the Laurentian Great Lakes.
Transfer efficiency (TE) is introduced as a model output that can be used to characterize the relative ability of chemicals to be transported in the environment and deposited to specific target ecosystems. We illustrate this concept by applying the Berkeley-Trent North American contaminant fate model (BETR North America) to identify organic chemicals with properties that result in efficient atmospheric transport and deposition to the Laurentian Great Lakes. By systematically applying the model to hypothetical organic chemicals that span a wide range of environmental partitioning properties, we identify combinations of properties that favor efficient transport and deposition to the Lakes. Five classes of chemicals are identified based on dominant transport and deposition pathways, and specific examples of chemicals in each class are identified and discussed. The role of vegetation in scavenging chemicals from the atmosphere is assessed, and found to have a negligible influence on transfer efficiency to the Great Lakes. Results indicate chemicals with octanol-water (K(ow)) and air-water (K(aw)) partition coefficients in the range of 10(5)-10(7) and 10(-4)-10(-1) combine efficient transport and deposition to the Great Lakes with potential for biaccumulation in the aquatic food web once they are deposited. A method of estimating the time scale for atmospheric transport and deposition process is suggested, and the effects of degrading reactions in the atmosphere and meteorological conditions on transport efficiency of different classes of chemicals are discussed. In total, this approach provides a method of identifying chemicals that are subject to long-range transport and deposition to specific target ecosystems as a result of their partitioning and persistence characteristics. Supported by an appropriate contaminant fate model, the approach can be applied to any target ecosystem of concern.


Investigations into microsporidian methionine aminopeptidase type 2: a therapeutic target for microsporidiosis.
The Microsporidia have been reported to cause a wide range of clinical diseases particularly in patients that are immunosuppressed. They can infect virtually any organ system and cases of gastrointestinal infection, encephalitis, ocular infection, sinusitis, myositis and disseminated infection are well described in the literature. While benzimidazoles such as albendazole are active against many species of Microsporidia, these drugs do not have significant activity against Enterocytozoon bieneusi. Fumagillin, ovalicin and their analogues have been demonstrated to have antimicrosporidial activity in vitro and in animal models of microsporidiosis. Fumagillin has also been demonstrated to have efficacy in human infections due to E. bieneusi. Fumagillin is an irreversible inhibitor of methionine aminopeptidase type 2 (MetAP2). Homology cloning employing the polymerase chain reaction was used to identify the MetAP2 gene from the human pathogenic microsporidia Encephalitozoon cuniculi, Encephalitozoon hellem, Encephalitozoon intestinalis, Brachiola algerae and E. bieneusi. The full-length MetAP2 coding sequence was obtained for all of the Encephalitozoonidae. Recombinant E. cuniculi MetAP2 was produced in baculovirus and purified using chromatographic techniques. The in vitro activity and effect of the inhibitors bestatin and TNP-470 on this recombinant microsporidian MetAP2 was characterized. An in silico model of E. cuniculi MetAP2 was developed based on crystallographic data on human MetAP2. These reagents provide new tools for the development of in vitro assay systems to screen candidate compounds for use as new therapeutic agents for the treatment of microsporidiosis.


Identifying major congenital malformations in the UK General Practice Research Database (GPRD): a study reporting on the sensitivity and added value of photocopied medical records and free text in the GPRD.
Postmarketing teratogen surveillance is essential and requires a data source that can reliably capture a wide range of congenital malformations. The UK General Practice Research Database (GPRD) may have the potential to be used for this kind of surveillance. To assess the extent to which this database can be used to accurately identify major congenital malformations. This study was carried out as part of a broader study to compare data on anticonvulsant use and safety in pregnancy between the GPRD and a pregnancy registry. The study period ran from 1 January 1990 until 31 December 2006. Mother-baby pairs where the mother had a record of epilepsy, seizure or convulsion were identified using the GPRD computerized medical records. Infants of mother-baby pairs who had a record of a major congenital malformation were identified. Full photocopied paper medical records were requested from the infant's general practitioner and where this was not possible any data entries consisting of uncoded comments, so-called 'free text', in the electronic GPRD record were requested from the database provider. This additional information was then reviewed in order to determine the extent to which the congenital malformation diagnoses identified via the computerized records could be confirmed or rejected and then classified as being major or minor. Within the study population of 3869 live mother-baby pairs, 188 potentially major congenital malformations were identified from the GPRD computerized record relating to 161 unique individuals. Using a combination of photocopied medical records and free text it was possible to verify 160 malformations (85.1%) as the malformation indicated by the computerized records; this ranged from 91.7% of those cases verified using photocopied medical records and 77.9% of cases verified using free text. Of the verified congenital malformations, using a combination of computerized data, photocopied medical records and free text, it was possible to classify 78.1% as being major and 15.0% as minor, and this percentage was found to be the same for those cases reviewed by photocopied records and those where free text was used. The proportions of malformations that could be verified and those that could be classified as major or minor were found to vary by malformation class. The GPRD can be used to ascertain a wide range of congenital malformations. In many cases, when a malformation is identified in the GPRD via the computerized medical records, the malformation is likely to exist. However, in this study a small proportion of identified cases had to be excluded because they had been coded incorrectly or diagnostically ruled out. Therefore, depending on the congenital malformation of interest, verification of such malformations using photocopied medical records or free text is generally recommended.


The protective role of Ocimum basilicum L. (Basil) against aspirin-induced gastric ulcer in mice: Impact on oxidative stress, inflammation, motor deficits and anxiety-like behavior.
The gastroprotective effect of Ocimum basilicum L. (Basil) hexane extract (OBHE) in aspirin-induced gastric ulcers in mice and its ameliorative effect on behavioral alterations were determined. Pretreatment with OBHE (100 or 200 mg kg-1) or misoprostol (50 μg kg-1) alleviated the aspirin-induced oxidative stress by significantly decreasing (p < 0.001) gastric ulcer index scores (57, 76 and 79%), gastric TBARS (by 49, 51 and 52%), NO (21, 28 and 29%), H2O2 (24, 42 and 45%), and the serum pro-inflammatory mediator TNF-α (21, 53 and 53%) and IL-6 (29, 30 and 31%), as well as by markedly increasing gastric GSH (41, 61 and 70%), GSH-Px (21, 32 and 34%), GST (33, 63 and 70%), GR (90, 99 and 112%), CAT (167, 211 and 267%) and serum PGE-2 levels (22, 135 and 200%) and IL-4 (64, 81 and 104%), respectively, compared with the aspirin-treated group. Meanwhile, OBHE and misoprostol induced a significant decrease (p < 0.001) in the freezing time (53, 56 and 64%), and the grooming time (by 25, 43 and 44%), respectively, compared to the aspirin treated group. This study provides evidence that OBHE confers anxiolytic, antioxidant and anti-inflammatory prophylactic effects on aspirin-induced gastric ulcers. GC/MS was used for the characterization of OBHE components. Based on the findings of this study, basil may be used as a nutritional supplement or therapeutic drug to protect against aspirin-induced gastric ulcers, a common problem resulting from the use of aspirin.


Power packet transferability via symbol propagation matrix.
A power packet is a unit of electric power composed of a power pulse and an information tag. In Shannon's information theory, messages are represented by symbol sequences in a digitized manner. Referring to this formulation, we define symbols in power packetization as a minimum unit of power transferred by a tagged pulse. Here, power is digitized and quantized. In this paper, we consider packetized power in networks for a finite duration, giving symbols and their energies to the networks. A network structure is defined using a graph whose nodes represent routers, sources and destinations. First, we introduce the concept of a symbol propagation matrix (SPM) in which symbols are transferred at links during unit times. Packetized power is described as a network flow in a spatio-temporal structure. Then, we study the problem of selecting an SPM in terms of transferability, that is, the possibility to represent given energies at sources and destinations during the finite duration. To select an SPM, we consider a network flow problem of packetized power. The problem is formulated as an M-convex submodular flow problem which is a solvable generalization of the minimum cost flow problem. Finally, through examples, we verify that this formulation provides reasonable packetized power.


Biomarkers of folate status in NHANES: a roundtable summary.
A roundtable to discuss the measurement of folate status biomarkers in NHANES took place in July 2010. NHANES has measured serum folate since 1974 and red blood cell (RBC) folate since 1978 with the use of several different measurement procedures. Data on serum 5-methyltetrahydrofolate (5MTHF) and folic acid (FA) concentrations in persons aged ≥60 y are available in NHANES 1999-2002. The roundtable reviewed data that showed that folate concentrations from the Bio-Rad Quantaphase II procedure (Bio-Rad Laboratories, Hercules, CA; used in NHANES 1991-1994 and NHANES 1999-2006) were, on average, 29% lower for serum and 45% lower for RBC than were those from the microbiological assay (MA), which was used in NHANES 2007-2010. Roundtable experts agreed that these differences required a data adjustment for time-trend analyses. The roundtable reviewed the possible use of an isotope-dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) measurement procedure for future NHANES and agreed that the close agreement between the MA and LC-MS/MS results for serum folate supported conversion to the LC-MS/MS procedure. However, for RBC folate, the MA gave 25% higher concentrations than did the LC-MS/MS procedure. The roundtable agreed that the use of the LC-MS/MS procedure to measure RBC folate is premature at this time. The roundtable reviewed the reference materials available or under development at the National Institute of Standards and Technology and recognized the challenges related to, and the scientific need for, these materials. They noted the need for a commutability study for the available reference materials for serum 5MTHF and FA.


Design, Formulation, and Physicochemical Evaluation of Montelukast Orally Disintegrating Tablet.
Orally disintegrating tablets (ODTs) are a modern form of tablets that when placed in the oral cavity, disperses rapidly. These tablets have advantages, particularly good applications for children and old patients who have a complication in chewing or swallowing solid dosage forms. The aim of this study was to design, formulate, and evaluate the physicochemical properties of 5 mg montelukast ODTs for the prevention of asthma and seasonal allergies. Formulations were prepared with different amounts of super disintegrating agents and effervescent bases as disintegrant agents. Flowability and compressibility of mixed powders were evaluated. The prepared formulations were tested for hardness, thickness, friability, weight variation, drug content, wetting time, disintegration time, dissolution study, and moisture uptake studies. The compressibility index and angle of repose were in the range of 15.87%-23.43% and 32.93-34.65, respectively. Hardness, thickness, friability, wetting time, and content uniformity of formulations were in the range of 33.7-37.1 N, 3.00-3.81 mm, 0.27%-0.43%, 31-50 s and 96.28%-99.90%, respectively. Disintegration time of the tablets prepared with super disintegrating agents, effervescent bases, and combination of two were in the range of 30-50, more than 60 and 20-36 s, respectively. Mixture of powders and tablets passed all the specified tests. The results showed formulations prepared by super disintegrating agents and super disintegrating agents with effervescent bases had shorter disintegration time compared to formulations with effervescent bases alone.


P-glycoprotein, breast cancer resistance protein, Organic Anion Transporter 3, and Transporting Peptide 1a4 during blood-brain barrier maturation: involvement of Wnt/β-catenin and endothelin-1 signaling.
Our current knowledge about drug transporters in the maturational brain is very limited. In this study, we provide a comprehensive overview of the expression and activity profile of P-glycoprotein (P-gp), Breast Cancer Resistance Protein (bcrp), Organic Anion Transporter 3 (oat3), and Transporting Peptide 1a4 (oatp1a4) transporters during blood-brain barrier (BBB) maturation. Gene and protein expressions of the analyzed transporters increase as the brain matures, with no variation in their activity for P-gp and bcrp, while the transport activity of oat3 and oatp1a4 increases during brain maturation from preterm up to adulthood. For the first time, we illustrate a downregulation of nuclear β-catenin expression in brain capillaries when bcrp, P-gp, oat3, and oatp1a4 transporters are at their highest expression levels. In vivo activation of β-catenin in rat brains, by intracerebroventricular (ICV) injection of a GSK-3 inhibitor, enhances the activity of P-gp, bcrp, oat3, and oatp1a4. Interestingly, in an in vitro BBB model consisting of a coculture of primary endothelial brain cells with astrocytes or in vivo, activation of β-catenin enhances the mRNA expression of ET-1. Interestingly, blocking the ETA receptor for endothelin-1 in vivo by ICV injection of a ETA antagonist decreases transporter activity mediated by the activation of β-catenin. These findings shed light on the role of an interaction between β-catenin and endothelin-1 signaling in the regulation of these transporters at the BBB.


The Human-Specific BOLA2 Duplication Modifies Iron Homeostasis and Anemia Predisposition in Chromosome 16p11.2 Autism Individuals.
Human-specific duplications at chromosome 16p11.2 mediate recurrent pathogenic 600 kbp BP4-BP5 copy-number variations, which are among the most common genetic causes of autism. These copy-number polymorphic duplications are under positive selection and include three to eight copies of BOLA2, a gene involved in the maturation of cytosolic iron-sulfur proteins. To investigate the potential advantage provided by the rapid expansion of BOLA2, we assessed hematological traits and anemia prevalence in 379,385 controls and individuals who have lost or gained copies of BOLA2: 89 chromosome 16p11.2 BP4-BP5 deletion carriers and 56 reciprocal duplication carriers in the UK Biobank. We found that the 16p11.2 deletion is associated with anemia (18/89 carriers, 20%, p = 4e-7, OR = 5), particularly iron-deficiency anemia. We observed similar enrichments in two clinical 16p11.2 deletion cohorts, which included 6/63 (10%) and 7/20 (35%) unrelated individuals with anemia, microcytosis, low serum iron, or low blood hemoglobin. Upon stratification by BOLA2 copy number, our data showed an association between low BOLA2 dosage and the above phenotypes (8/15 individuals with three copies, 53%, p = 1e-4). In parallel, we analyzed hematological traits in mice carrying the 16p11.2 orthologous deletion or duplication, as well as Bola2+/- and Bola2-/- animals. The Bola2-deficient mice and the mice carrying the deletion showed early evidence of iron deficiency, including a mild decrease in hemoglobin, lower plasma iron, microcytosis, and an increased red blood cell zinc-protoporphyrin-to-heme ratio. Our results indicate that BOLA2 participates in iron homeostasis in vivo, and its expansion has a potential adaptive role in protecting against iron deficiency.


Collateral circulation is an independent radiological predictor of outcome after thrombolysis in acute ischaemic stroke.
We tested the hypothesis that the type of vascular occlusion, recanalisation and collateralisation are predictive of outcome after thrombolytic therapy in acute ischaemic stroke. We carried out angiography and local intra-arterial (97) or systemic (14) thrombolysis within 6 h of the onset in patients with an ischaemic stroke in the territory of the internal carotid artery. Early ischaemic signs (EIS) on pretreatment CT and angiographic findings were classified and analysed in relation to clinical outcome at 3 months. A favourable outcome (Barthel index [BI]>/= 90) was found in 40% of patients with an occlusion of the middle cerebral artery trunk whereas intracranial occlusion of the internal carotid artery ("carotid T occlusion") was followed by death or severe disability (BI<50) in 87%. Significant univariate predictors of favourable outcome were occlusion type ( P<0.01), recanalisation ( P<0.01) and collateralisation ( P<0.01). However, multivariate analysis revealed a significant relationship only between collateralisation and favourable outcome (odds ratio 5.9, 95% confidence interval 1.3-26.7, P=0.02). EIS were not predictive in either case. Occlusion type and recanalisation, are related to outcome only if adequate collateralisation prevents infarction until recanalisation occurs.


Relationship between longitudinal and radial contractility in subclinical diabetic heart disease.
Subclinical left ventricular (LV) dysfunction may be identified by reduced longitudinal contraction. We sought to define the effects of subclinical LV dysfunction on radial contractility in 53 patients with diabetes mellitus with no LV hypertrophy, normal ejection fraction and no ischaemia as assessed by dobutamine echocardiography, in comparison with age-matched controls. Radial peak myocardial systolic velocity (Sm) and early diastolic velocity (Em), strain and strain rate were measured in the mid-posterior and mid-anteroseptal walls in parasternal views and each variable was averaged for individual patients (radial contractility). These variables were also measured in the mid-posterior and mid-anteroseptal walls in the apical long-axis view and each variable was averaged for individual patients (longitudinal contractility). Mean radial Sm, strain and strain rate were significantly increased in diabetic patients (2.9 +/- 0.6 cm/s, 28 +/- 5% and 1.8 +/- 0.4 s(-1) respectively) compared with controls (2.4 +/- 0.7 cm/s, 23 +/- 4% and 1.6 +/- 0.3 s(-1) respectively; all P<0.001), but there was no difference in Em (3.3 +/- 1.2 compared with 3.1 +/- 1.1 cm/s, P=not significant). In contrast, longitudinal Sm, Em, strain and strain rate were significantly lower in diabetic patients (3.6 +/- 1.1 cm/s, 4.3 +/- 1.6 cm/s, 21 +/- 4% and 1.6 +/- 0.3 s(-1) respectively) than in controls (4.3 +/- 1.0 cm/s, 5.7 +/- 2.3 cm/s, 26 +/- 4% and 1.9 +/- 0.3 s(-1) respectively; all P< or =0.001). Thus radial contractility appears to compensate for reduced longitudinal contractility in subclinical LV dysfunction occurring in the absence of ischaemia or LV hypertrophy.


Large, identical, tandem repeating units in the C protein alpha antigen gene, bca, of group B streptococci.
Group B Streptococcus (GBS) is the leading cause of neonatal sepsis and meningitis in the United States. The surface-associated C protein alpha antigen of GBS is thought to have a role in both virulence and immunity. We previously cloned the C protein alpha antigen structural gene (named bca for group B, C protein, alpha) into Escherichia coli. Western blots of both the native alpha antigen and the cloned gene product demonstrate a regularly laddered pattern of heterogeneous polypeptides. The nucleotide sequence of the bca locus reveals an open reading frame of 3060 nucleotides encoding a precursor protein of 108,705 Da. Cleavage of a putative signal sequence of 41 amino acids yields a mature protein of 104,106 Da. The 20,417-Da N-terminal region of the alpha antigen shows no homology to previously described protein sequences and is followed by a series of nine tandem repeating units that make up 74% of the mature protein. Each repeating unit is identical and consists of 82 amino acids with a molecular mass of 8665 Da, which is encoded by 246 nucleotides. The size of the repeating units corresponds to the observed size differences in the heterogeneous ladder of alpha C proteins expressed by GBS. The C-terminal region of the alpha antigen contains a membrane anchor domain motif that is shared by a number of Gram-positive surface proteins. The large region of identical repeating units in bca defines protective epitopes and may play a role in generating phenotypic and genotypic diversity of the alpha antigen.


The importance of acute luminal diameter in determining restenosis after coronary atherectomy or stenting.
We evaluated native coronary arteries treated by directional coronary atherectomy or balloon-expandable stent placement in an effort to derive a quantitative geometric model relating the luminal diameter immediately after intervention to that present 6 months later. The minimal luminal diameter of each lesion was measured before and immediately after intervention in 102 single Palmaz-Schatz stents and 134 directional atherectomies, 192 (81%) of which had repeat angiographic measurement of minimal luminal diameter 6 months after the intervention. The immediate enlargement in luminal diameter produced by the intervention (acute gain) and the subsequent reduction in luminal diameter from the time of intervention to 6 months of follow-up (late loss) were calculated. Luminal diameter increased from 0.69 +/- 0.40 mm to 3.11 +/- 0.64 mm (acute gain, 2.41 +/- 0.64 mm) after intervention, providing an immediate postprocedure residual stenosis of 1 +/- 14% relative to a reference diameter of 3.13 +/- 0.65 mm. At 6-month follow-up, the late luminal diameter was 1.97 +/- 0.92 mm (late loss, 1.13 +/- 0.89 mm), yielding a late diameter stenosis of 36 +/- 26%. The restenosis rate (according to the traditional definition of diameter stenosis > or = 50%) was 30%. Multivariable analysis demonstrated that late luminal diameter (p = 0.02), late percent stenosis (p = 0.04), and restenosis (according to a > 50% definition, p = 0.04) were each strongly associated with the luminal diameter present immediately after the procedure. Whereas late luminal diameter was also influenced by reference artery size and the vessel treated (left anterior descending versus right coronary artery), reference vessel size was rejected by the multivariable models of late percent stenosis and binary restenosis after they were adjusted for the effect of postprocedure luminal diameter. Once adjusted for postprocedure luminal diameter, neither late luminal diameter nor late loss was found to be independently determined by which device was used (atherectomy versus stents). Rather, late loss was determined independently by the immediate postprocedure luminal diameter (p = 0.005) and the postprocedure percent stenosis (p = 0.02). Although late loss thus increased with acute gain, the net beneficial effect of increased acute gain was maintained: Late loss was only a fraction (0.47) of acute gain, so the ability of a larger postprocedure luminal diameter to reduce the probability of subsequent restenosis was preserved. This quantitative model demonstrates that the late coronary lumen diameter and the probability of restenosis after Palmaz-Schatz stenting or directional atherectomy are influenced strongly by the lumen diameter present immediately after the procedure rather than by the specific device used. Although the influence of a larger acute result on reduced restenosis appears to be well established in this treatment population, the interplay among the multiple other biological influences on restenosis limits the ability to predict the probability of restenosis for the individual patient based on a large acute result alone. Future studies of restenosis, however, can further refine this multivariable quantitative model by adjusting for the effects of other clinical variables, mechanical interventions, or drug therapies in addition to the clear effect of postprocedure luminal diameter.


Structure of the ribosome with elongation factor G trapped in the pretranslocation state.
During protein synthesis, tRNAs and their associated mRNA codons move sequentially on the ribosome from the A (aminoacyl) site to the P (peptidyl) site to the E (exit) site in a process catalyzed by a universally conserved ribosome-dependent GTPase [elongation factor G (EF-G) in prokaryotes and elongation factor 2 (EF-2) in eukaryotes]. Although the high-resolution structure of EF-G bound to the posttranslocation ribosome has been determined, the pretranslocation conformation of the ribosome bound with EF-G and A-site tRNA has evaded visualization owing to the transient nature of this state. Here we use electron cryomicroscopy to determine the structure of the 70S ribosome with EF-G, which is trapped in the pretranslocation state using antibiotic viomycin. Comparison with the posttranslocation ribosome shows that the small subunit of the pretranslocation ribosome is rotated by ∼12° relative to the large subunit. Domain IV of EF-G is positioned in the cleft between the body and head of the small subunit outwardly of the A site and contacts the A-site tRNA. Our findings suggest a model in which domain IV of EF-G promotes the translocation of tRNA from the A to the P site as the small ribosome subunit spontaneously rotates back from the hybrid, rotated state into the nonrotated posttranslocation state.


Effects of laser in situ keratomileusis on mental health-related quality of life.
The aims of our study were to investigate whether laser in situ keratomileusis (LASIK) improves health-related quality of life (HRQoL) and to identify factors that affect postoperative HRQoL. A total of 213 Japanese patients who underwent primary LASIK were analyzed in this study. The average age of patients was 35.0±9.4 years. The subjects were asked to answer questions regarding subjective quality of vision, satisfaction, and quality of life (using the Japanese version of 36-Item Short Form Health Survey Version 2) at three time points: before LASIK, 1 month after LASIK, and 6 months after LASIK. Longitudinal changes over 6 months in the outputs of mental component summary (MCS) score and the physical component summary (PCS) score from the 36-Item Short Form Health Survey Version 2 questionnaire were compared between time points using a linear mixed-effects model. Delta MCS and PCS were calculated by subtracting the postoperative score (1 month after LASIK) from the preoperative score. Preoperative and postoperative factors associated with a change in the MCS score or PCS score were evaluated via a linear regression model. The preoperative MCS score was 51.0±9.4 and increased to 52.0±9.8 and 51.5±9.6 at 1 month and 6 months after LASIK, respectively, and the trend for the change from baseline in MCS through 6 months was significant (P=0.03). PCS score did not change following LASIK. Delta MCS was significantly negatively associated with preoperative spherical equivalent, axial length, and postoperative quality of vision, after adjusting for potential confounding factors. Mental HRQoL is not lost with LASIK, and LASIK may improve mental HRQoL. Preoperative axial length may predict postoperative mental HRQoL.


In vitro effects of desoxycorticosterone on vascular smooth muscle.
We present evidence in accord with the observations of S. Kalsner (Br. J. Pharmacol. 36: 582-593, 1969) that in the rabbit aorta, desoxycorticosterone (DOC) potentiates the contractile response to certain catecholamines by inhibiting their degradation by catechol-O-methyltransferase. In contrast, DOC depresses the contractile responses in rat aorta and tail arteries. To elucidate the mechanism of this depression the effect of DOC was evaluated under various conditions. DOC depressed the contractile response to epinephrine, phenylephrine, KCl, and angiotensin II. The depression was unaltered by ouabain or by a potassium-free solution, indicating that DOC did not produce its depression by altering Na-K-ATPase activity. The depression is unaltered in a chloride-free solution, demonstrating that the DOC effect is not caused by a change in membrane permeability to chloride. Radioisotope studies demonstrate that DOC does not alter membrane permeability to potassium. Removal of extracellular calcium with EGTA (ethylene glycol-bis (beta-aminoethyl ether) N, N'-tetraacetic acid) significantly reduced the magnitude of the DOC depression. Indirect evidence is presented suggesting that DOC might increase calcium binding to the plasma membrane, resulting in its stabilization and hence in a depression of the contractile response.


Well-differentiated villoglandular adenocarcinoma of the uterine cervix: assessment of cytological features by histological subtypes.
Well-differentiated villoglandular adenocarcinoma (VGA) of the cervix involves papillae lined by different types of epithelial cells that are histologically subclassified into endocervical, endometrioid, or intestinal subtypes. The objective of the current study was to evaluate the definite cytological features of VGA by histological subtype. We examined 8 cervical smears from patients confirmed to have pure VGA and classified them into the 3 histological subtypes. The cervical smears were highly cellular and had a relatively clean background. The nuclei had minimal anisonucleosis and fine granular chromatin with almost inconspicuous nucleoli. The characteristic findings of the endocervical type were a palisading arrangement consisting of columnar or spindle-shaped cells with apical or elongated nuclei. Small but clear nucleoli were identified only in the endocervical type. In the endometrioid type, tumor cells consisted of cohesive sheets with smooth edges and very round nuclei. Cytoplasmic vacuolation was never observed in the endometrioid type. The tumor cells in the intestinal type were prominent with abundant cytoplasmic mucin. We demonstrated that the cytological features of this tumor can vary depending on the histological subtype and one should be aware of these features in order to improve diagnostic accuracy.


The Bipartisan Patient Protection Act: greater liability on managed care plans.
Mrs. Mayers' article notes the substantial differences that exist between the Senate and the House of Representatives' version of the Bipartisan Patient Protection Act of 2001. While observing the remedies made available to participants, beneficiaries, or enrollees under both bills, she shows that the Senate bill places greater liability on managed care plans because it favors consumer protection, while the House of Representatives' bill does not. In order to develop an understanding of why an act of this nature is needed, Mrs. Mayers provides a brief historical overview of how managed care entities developed. She also examines the Employee Retirement Income Security Act ("ERISA") and proposes amendments to them. She concludes her article by raising an even deeper concern, and that is: what happens to individuals without access to health care coverage.


Reconstructing an epistemological itinerary: environmental theories of variation in Roubaud's experiments on Glossina flies and Anopheles, 1900-1938.
This paper addresses the theories and debates concerning the influence of environment on vectors and species variation. In particular, it focuses on theories about how climate and domesticated animals affected vectors that transmitted sleeping sickness and malaria. Emile Roubaud (1882-1962), a Pasteurian entomologist, worked on the adaptation and variation of Glossina fly races in order to elaborate environmental interventions for sleeping sickness campaigns in Africa. He then developed the theory concerning Glossina flies' biting preferences for livestock, and the implications of such preferences for human protection against sleeping sickness transmission. Subsequently, he extended this theory about insect biting preferences to malaria in Europe. He thus used one disease model, the sleeping sickness complex, and extended it to another, the malaria complex. He subsequently became interested into zoophilic races of Anopheles maculipennis and advocated the hypothesis that the zoophilic Anophelines' maxillary index was a decisive feature in malaria transmission, for it could help preventing humans from the bite of the Anopheles vector. The paper also analyzes how these theories were received and debated at the time of their publication in scientific journals and proceedings.


Cancer stem cell targeted therapies.
In normal dividing tissues, cell homeostasis is maintained by rare cellular elements, the stem cells, that have the unique property of self-renewal and differentiation to generate a population of functionally mature tissue elements. Recent studies carried out in the last three decades support the existence of stem cells also in tumors, the so-called cancer stem cells. Cancer stem cells have the property of initiating and maintaining tumor growth, are able to self-renew and to differentiate, are the main drivers of intra- and inter-tumoral heterogeneity and the main cellular mediators of drug resistance, leading to tumor recurrence and metastasis. Cancer stem cells can be identified in many tumors according to specific immunophenotypic features, but cancer stemness cannot be defined as a fixed property, due to cancer plasticity. For these properties, cancer stem cells represent attractive targets for developing new anti-cancer therapies and there is supporting evidence that the combination of conventional anticancer therapies with drugs targeting cancer stem cells could lead to cancer eradication. Ongoing studies in some tumors strongly support the clinical utility of developing efficient strategies of cancer stem cell targeting.


Ureaplasma parvum undergoes selection in utero resulting in genetically diverse isolates colonizing the chorioamnion of fetal sheep.
Ureaplasmas are the microorganisms most frequently isolated from the amniotic fluid of pregnant women and can cause chronic intrauterine infections. These tiny bacteria are thought to undergo rapid evolution and exhibit a hypermutatable phenotype; however, little is known about how ureaplasmas respond to selective pressures in utero. Using an ovine model of chronic intraamniotic infection, we investigated if exposure of ureaplasmas to subinhibitory concentrations of erythromycin could induce phenotypic or genetic indicators of macrolide resistance. At 55 days gestation, 12 pregnant ewes received an intraamniotic injection of a nonclonal, clinical Ureaplasma parvum strain followed by (i) erythromycin treatment (intramuscularly, 30 mg/kg/day, n = 6) or (ii) saline (intramuscularly, n = 6) at 100 days gestation. Fetuses were then delivered surgically at 125 days gestation. Despite injecting the same inoculum into all the ewes, significant differences between amniotic fluid and chorioamnion ureaplasmas were detected following chronic intraamniotic infection. Numerous polymorphisms were observed in domain V of the 23S rRNA gene of ureaplasmas isolated from the chorioamnion (but not the amniotic fluid), resulting in a mosaiclike sequence. Chorioamnion isolates also harbored the macrolide resistance genes erm(B) and msr(D) and were associated with variable roxithromycin minimum inhibitory concentrations. Remarkably, this variability occurred independently of exposure of ureaplasmas to erythromycin, suggesting that low-level erythromycin exposure does not induce ureaplasmal macrolide resistance in utero. Rather, the significant differences observed between amniotic fluid and chorioamnion ureaplasmas suggest that different anatomical sites may select for ureaplasma subtypes within nonclonal, clinical strains. This may have implications for the treatment of intrauterine ureaplasma infections.


Immunoreactive epidermal growth factor receptors are present in gastrointestinal epithelial cells of preterm infants with necrotising enterocolitis.
Epidermal growth factor (EGF) affects epithelial cell proliferation, differentiation and migration in the gastrointestinal tract of experimental animals, and increases proliferation when given intravenously to children with congenital microvillous atrophy or necrotising enteritis. The aim of the present study is to determine whether EGF receptors (EGFR) are present in the gut epithelium of preterm infants, and to discover whether neonatal necrotising enterocolitis (NEC) is associated with the absence of EGFR from mucosal cells. Tissues were taken from involved colon and small intestine of four preterm infants with NEC, and control tissues were taken from four other neonates who had laparatomies for congenital malformations. Sections of the tissues were examined histopathologically after treatment with a monoclonal antibody against the external domain of the EGFR (Zymed Laboratories, San Francisco, CA, USA). Histopathological examination confirmed diagnosis of NEC in the involved bowel and controls showed appearance within normal limit. Immunoreactive EGFR were present on the epithelial cells of both the colon and small intestine, localised on the basolateral membrane of the cells of both subject and the controls. There was no apparent reduction in expression compared with controls. NEC in preterm infants is not associated with absence of EGFR. The presence of EGFR in gut epithelial cells raises the possibility of using EGF for prophylaxis or treatment of NEC.


Immunostimulating effects of extract of Acanthopanax sessiliflorus.
As malfunction/absence of immune cells causes a variety of immunosuppressive disorders and chemical synthetic drugs for curing these diseases have many adverse effects, vigorous studies are being conducted. The Acanthopanax family has been used as traditional medicines for gastric ulcer, diabetes, etc. and culinary materials in East-South Asia. In this study, the immunostimulating properties of A. sessiliflorus were evaluated. A. sessiliflorus increased not only the splenocyte number but also immune-related cytokines such as TNF-α. However, it could not upregulate the expressions of IFN-γ and IL-2. A. sessiliflorus increased the swimming time, and comparison of organ weights relative to body weights for immune-related organs such as the spleen and thymus after a forced swim test showed that it could recover the spleen and thymus weights. It also increased the expression of TNF-α and slightly increased the concentration of IFN-γ but not IL-2. From the results, we concluded that as A. sessiliflorus has not only a host defense effect but also a stress-ameliorating property, further study it will be a promising material of immunostimulating material.


Kinetic and Theoretical Studies of Beta-Lactone Reactivity-A Quantitative Scale for Biological Application.
Natural products comprise a rich source for bioactive molecules with medicinal relevance. Many of these contain electrophilic scaffolds that bind conserved enzyme active sites covalently. Prominent examples include beta-lactams and beta-lactones, which specifically acylate serine residues in diverse peptidases. Although these scaffolds appear similar, their bioactivities and corresponding protein targets vary. To quantify and dissect these differences in bioactivities, the kinetics of the reactions of beta-butyrolactone with a set of reference amines in buffered aqueous solution at 37 °C have been analyzed. Different product ratios of C1 versus C3 attack on the beta-butyrolactone have been observed, depending on the aliphatic or aromatic nature of the standard amine used. Quantum mechanics/molecular mechanics (QM/MM) calculations reveal that a H3 O+ molecule has a crucial role in stabilizing C3 attack by aniline, through coordination of the lactone ring oxygen. In agreement with their weak proteome reactivity, monocyclic beta-lactams did not react with the set of standard nucleophiles studied herein. Bicyclic beta-lactams, however, exhibited a lower activation barrier, and thus, reacted with standard nucleophiles. This study represents a starting point for semiquantitative reactivity scales for natural products, which, in analogy to chemical reactivity scales, will provide predictions for electrophilic modifications in biological systems.


Clinical phase I intratumoral administration of two recombinant ALVAC canarypox viruses expressing human granulocyte-macrophage colony-stimulating factor or interleukin-2: the transgene determines the composition of the inflammatory infiltrate.
Immunotherapy employs cytokines for modifying local inflammatory reactions. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to activate dendritic cells, macrophages, and granulocytes leading to clinical trials using GM-CSF-based cancer vaccine approaches. Interleukin-2 (IL-2) is an important T cell stimulatory cytokine approved as exogenous antitumor agent. The ALVAC viral vector system uses a recombinant canarypox virus for local gene expression. We report a phase I clinical trial using intratumoral administration of ALVAC GM-CSF or ALVAC IL-2 in skin metastases of melanoma or leiomyosarcoma. ALVAC GM-CSF and ALVAC IL-2 were injected at 107.12 and 106.92, 50% cell culture infectious dose in eight metastases with acceptable tolerability. Local and systemic inflammatory reactions were observed. The transgene determined the local infiltrate: GM-CSF induced monocyte and macrophage enrichment of the peritumoral inflammatory infiltrate, whereas IL-2 increased local T lymphocytes. Stable disease of injected lesions was seen after ALVAC GM-CSF application, whereas ALVAC IL-2 treatment led to partial regression in three out of eight injected tumors, accompanied by decreased expression of melanocytic antigens. Local GM-CSF expression could be induced. In summary, ALVAC GM-CSF and ALVAC IL-2 injections are safe and can mediate local biologic and immunologic effects.


A comparative study of the polyaniline thin films produced by the cluster beam deposition and laser ablation methods.
Polyaniline (PANI) thin films have been prepared by applying the novel neutral and ionized cluster beam deposition (NCBD and ICBD) methods and the pulsed laser deposition (PLD) technique to the PANI samples of half-oxidized emeraldine base (EB-PANI) and protoemeraldine base forms in a high-vacuum condition. Characterization of the oxidation states and structural changes of pristine and doped thin films has been performed by Fourier transform infrared spectroscopy, ultraviolet-visible spectroscopy, and x-ray photoelectron spectroscopy. Spectroscopic measurements demonstrate that the dominant structure of NCBD and ICBD thin films corresponds to the reduced leucoemeraldine base state, whereas the chemical composition of PLD thin films depends critically on the laser fluence and the molecular weight of PANI target. The congruent deposition is only obtained for the PLD films deposited by the laser-induced decomposition of the low-molecular-weight targets in the low to intermediate fluence regime (below 100 mJ/cm2 with a pulse duration of 7 ns). The surface morphology examined by atomic force microscopy measurements shows that the cluster and laser beams are effective in producing smooth, uniform polymeric thin films. After I2 and HCl doping, the electrical conductivities of the NCBD, ICBD, and particularly PLD thin films are increased significantly. The higher conductivity of PLD films is ascribed to higher amounts of quinoid di-imine doping sites in the EB-PANI state, and the overall structure-conductivity characteristics are consistent with the spectroscopic observations.


Prediction of 90-day mortality in older patients after discharge from an emergency department: a retrospective follow-up study.
Older people frequently attend the emergency department (ED) and have a high risk of poor outcome as compared to their younger counterparts. Our aim was to study routinely collected clinical parameters as predictors of 90-day mortality in older patients attending our ED. We conducted a retrospective follow-up study at the Leiden University Medical Center (The Netherlands) among patients aged 70 years or older attending the ED in 2012. Predictors were age, gender, time and way of arrival, presenting complaint, consulting medical specialty, vital signs, pain score and laboratory testing. Cox regression analyses were performed to analyse the association between these predictors and 90-day mortality. Three thousand two hundred one unique patients were eligible for inclusion. Ninety-day mortality was 10.5 % for the total group. Independent predictors of mortality were age (hazard ratio [HR] 1.06, 95 % confidence interval [95 % CI] 1.04-1.08), referral from another hospital (HR 2.74, 95 % CI 1.22-6.11), allocation to a non-surgical specialty (HR: 1.55, 95 % CI 1.13-2.14), increased respiration rate (HR up to 2.21, 95 % CI 1.25-3.92), low oxygen saturation (HR up to 1.96, 95 % CI 1.19-3.23), hypothermia (HR 2.27, 95 % CI 1.28-4.01), fever (HR 0.43, 95 % CI 0.24-0.75), high pain score (HR 1.55, 95 % CI 1.03-2.32) and the indication to perform laboratory testing (HR 3.44, 95 % CI 2.13-5.56). Routinely collected parameters at the ED can predict 90-day mortality in older patients presenting to the ED. This study forms the first step towards creating a new and simple screening tool to predict and improve health outcome in acutely presenting older patients.


Endophilin B is required for the Drosophila oocyte to endocytose yolk downstream of Oskar.
The nutritional environment is crucial for Drosophila oogenesis in terms of controlling hormonal conditions that regulate yolk production and the progress of vitellogenesis. Here, we discovered that Drosophila Endophilin B (D-EndoB), a member of the endophilin family, is required for yolk endocytosis as it regulates membrane dynamics in developing egg chambers. Loss of D-EndoB leads to yolk content reduction, similar to that seen in yolkless mutants, and also causes poor fecundity. In addition, mutant egg chambers exhibit an arrest at the previtellogenic stage. D-EndoB displayed a crescent localization at the oocyte posterior pole in an Oskar-dependent manner; however, it did not contribute to pole plasm assembly. D-EndoB was found to partially colocalize with Long Oskar and Yolkless at the endocytic membranes in ultrastructure analysis. Using an FM4-64 dye incorporation assay, D-EndoB was also found to promote endocytosis in the oocyte. When expressing the full-length D-endoB(FL) or D-endoB(ΔSH3) mutant transgenes in oocytes, the blockage of vitellogenesis and the defect in fecundity in D-endoB mutants was restored. By contrast, a truncated N-BAR domain of the D-EndoB only partially rescued these defects. Taken together, these results allow us to conclude that D-EndoB contributes to the endocytic activity downstream of Oskar by facilitating membrane dynamics through its N-BAR domain in the yolk uptake process, thereby leading to normal progression of vitellogenesis.


Biocatalytic Nanocomposites for Combating Bacterial Pathogens.
Bacterial infections remain a major public health concern. However, broad-spectrum antibiotics largely target redundant mechanisms of bacterial survival and lead to gained resistance owing to microbial evolution. New methods are needed to attack bacterial infections, and we have only begun to seek out nature's vast arsenal of antimicrobial weapons. Enzymes offer one such weapon, and their diversity has been exploited to kill bacteria selectively through unique targets, particularly in bacterial cell walls, as well as nonselectively through generation of bactericidal molecules. In both approaches, microbial resistance has largely been absent, which bodes well for its potential use in human therapeutics. Furthermore, enzyme stabilization through conjugation to nanoscale materials and incorporation into polymeric composites enable their use on surfaces to endow them with antimicrobial properties. Here, we highlight the use of enzymes as antimicrobial agents, including applications that may prove effective in new therapeutics and through control of key societal infrastructures.


Spatiotemporal digital microholography.
We develop the theoretical background of a holographic method in which the hologram is sampled simultaneously in space and in time by a charge-coupled device (CCD) sensor. With the use of temporal heterodyning (rather than spatial heterodyning, which is employed in conventional holography), in-line, single-sideband holograms of fields having an arbitrary degree of spatial coherence are recorded in an exposure time that can theoretically be as short as four frames of the CCD. The method is applied to microholography and is shown to avoid the main drawbacks of conventional holographic microscopy, namely, the need for high-spatial-bandwidth detectors and for a high degree of spatial coherence, which unavoidably leads to speckle noise. The possibility of a posteriori aberration compensation is demonstrated, and experimental results are presented.


Medical therapy and intervention do not improve uncomplicated isolated mesenteric artery dissection outcomes over observation alone.
Isolated dissection of the mesenteric vessels is rare but increasingly recognized. This study aimed to evaluate patient characteristics, primary treatment, and subsequent outcomes of mesenteric dissection using multi-institutional data. All patients at participant hospitals between January 2003 and December 2015 with dissection of the celiac artery (or its branches) or dissection of the superior mesenteric artery (SMA) were included. Patients with an aortic dissection were excluded. Demographic, treatment, and follow-up data were collected. The primary outcomes included late vessel thrombosis (LVT) and aneurysmal degeneration (AD). Twelve institutions identified 227 patients (220 with complete treatment records) with a mean age of 55 ± 12.5 years. Median time to last follow up was 15 months (interquartile range, 3.8-32). Most patients were men (82% vs 18% women) and symptomatic at presentation (162 vs 65 asymptomatic). Isolated SMA dissection was more common than celiac artery dissection (n = 158 and 81, respectively). Concomitant dissection of both arteries was rare (n = 12). The mean dissection length was significantly longer in symptomatic patients than in asymptomatic patients in both the celiac artery (27 vs 18 mm; P = .01) and the SMA (64 vs 40 mm; P < .001). Primary treatment was medical in 146 patients with oral anticoagulation or antiplatelet therapy (n = 76 and 70, respectively), whereas 56 patients were observed. LVT occurred in six patients, and 16 patients developed AD (3% and 8%, respectively). For symptomatic patients without evidence of ischemia (n = 134), there was no difference in occurrence of LVT with medical therapy compared with observation alone (9% vs 0%; P = .35). No asymptomatic patient (n = 64) had an episode of LVT at 5 years. AD rates did not differ among symptomatic patients without ischemia treated with medical therapy or observed (9% vs 5%; P = .95). Surgical or endovascular intervention was performed in 18 patients (3 ischemia, 13 pain, 1 AD, 1 asymptomatic). Excluding the patients treated for ischemia, there was no difference in LVT with surgical intervention vs medical management (one vs five; P = .57). Asymptomatic patients with isolated mesenteric artery dissection may be observed and followed up with intermittent imaging. Symptomatic patients tend to have longer dissections than asymptomatic patients. Symptomatic isolated mesenteric artery dissection without evidence of ischemia does not require anticoagulation and may be treated with antiplatelet therapy or observation alone.