Association between blood cadmium levels and 10-year coronary heart disease risk in the general Korean population: the Korean National Health and Nutrition Examination Survey 2008-2010.
Non-occupational heavy metals are considered risk factors for coronary heart disease (CHD). Several recent epidemiologic studies have evaluated the relationship between non-occupational cadmium exposure and risk factors for cardiovascular disease (CVD). This study was designed to investigate the relationship between non-occupational cadmium exposure and risk factors for CHD using the Framingham estimate of 10 year CHD risk. The heavy metal dataset of the Korean National Health and Nutrition Examination Survey for 2008 through 2010, a cross-sectional survey of a representative sample of 4,668 non-institutionalized Koreans, was analyzed. Subjects were stratified into seven age groups to minimize the effects of age. The log-transformed blood cadmium concentrations were compared with the Framingham estimate of 10 year CHD risk in each age stratum. The Framingham estimate of 10 year CHD risk was significantly associated with the log-transformed blood cadmium concentrations (p<0.05) in all age groups of Korean men, with the lowest regression coefficient (0.254) for men aged 20 to <35 years and the highest (3.354) for men aged 55 to <60 years; similar results, however, were not observed in Korean women. After adjusting for survey year, age, and urinary cotinine concentration, the log-transformed blood cadmium levels among men aged 20 to <35, 40 to <45, 50 to <55, and 60 to <65 years were significantly associated with systolic blood pressure (p<0.05), but not with total and high density lipoprotein (HDL) cholesterol concentrations. Cadmium exposure, even at non-occupational levels, may be associated with CHD risk in men. Despite the declines in non-occupational cadmium exposure over the past several decades, more efforts are needed.


Are we born moral?
Reviews of: Hauser, Marc D. Moral minds: how nature designed our universal sense of right and wrong. (New York: Ecco, 2006); and Waal, F.B.M. de. Primates and philosophers: how morality evolved. (Princeton, N.J. : Princeton University Press, 2006).


The Back Injury Prevention Project pilot study. Assessing the effectiveness of back attack, an injury prevention program among nurses, aides, and orderlies.
The Back Injury Prevention Project was a pilot study of "Back Attack," an educational program designed to prevent back injuries among nurses, nurses' aides, and orderlies. The pilot tested program feasibility, developed and tested instruments, and generated preliminary data measuring program effectiveness. Fifty-five nurses, aides, and orderlies on two medical/surgical units at two Kaiser Permanente medical centers in Portland, Oregon participated in the study. Intervention group scores on the composite back pain and composite fatigue scales decreased relative to the control group, but this did not reach statistical significance. A 19% improvement in scores for quality of patient transfer was observed for the intervention group (P < .0003), while the control group did not show any significant improvement during the same time period. Results of the pilot suggest that the Back Attack program changes behavior at least in the short term. Further study will be necessary to determine if the behavior change persists and back pain and injury rates are subsequently reduced.


Molecular evolution of juvenile hormone esterase-like proteins in a socially exchanged fluid.
Socially exchanged fluids are a direct means by which an organism can influence conspecifics. It was recently shown that when workers of the carpenter ant Camponotus floridanus feed larval offspring via trophallaxis, they transfer Juvenile Hormone III (JH), a key developmental regulator, as well as paralogs of JH esterase (JHE), an enzyme that catalyzes the hydrolysis of JH. Here we combine proteomic, phylogenetic and selection analyses to investigate the evolution of this esterase subfamily. We show that Camponotus JHE-like proteins have undergone multiple duplications, experienced positive selection, and changed tissue localization to become abundantly and selectively present in trophallactic fluid. The Camponotus trophallactic esterases have maintained their catalytic triads and contain a number of positively-selected amino acid changes distributed throughout the protein, which possibly reflect an adaptation to the highly acidic trophallactic fluid of formicine ants. To determine whether these esterases might regulate larval development, we fed workers with a JHE-specific pharmacological inhibitor to introduce it into the trophallactic network. This inhibitor increased the likelihood of pupation of the larvae reared by these workers, similar to the influence of food supplementation with JH. Together, these findings suggest that JHE-like proteins have evolved a new role in the inter-individual regulation of larval development in the Camponotus genus.


Associations between Optic Disc Measures and Obstructive Sleep Apnea in Young Adults.
Obstructive sleep apnea (OSA) is linked to increased glaucoma risk in middle-aged and older adults. However, little is known about associations between OSA and glaucoma-related optic disc parameters in young adults. We explored associations between overnight polysomnography-derived measures of OSA and the optic disc in young adults. Cross-sectional cohort study. Eight hundred forty-eight adults 19 to 22 years of age. Participants underwent an ophthalmic examination that included OCT imaging of the optic disc and measurements of intraocular pressure, axial length, and refractive error. Participants then underwent an overnight polysomnography study that obtained measurements of apnea-hypopnea index (AHI), peripheral oxygen saturation level, and number of cortical arousals from sleep. Based on the AHI results, participants were grouped into no OSA (AHI < 5 events/hour), mild OSA (AHI ≥ 5 and <15 events/hour), moderate OSA (AHI ≥ 15 and <30 events/hour), or severe OSA (AHI ≥ 30 events/hour). Neuroretinal rim area, horizontal and vertical widths, and peripapillary retinal nerve fiber layer (RNFL) thickness. The median AHI result across the study cohort was 2.2 events per hour (interquartile range, 1.0-4.4 events/hour). Based on the AHI results, 178 participants (21.0%) demonstrated OSA: 150 with mild OSA, 26 with moderate OSA, and 2 with severe OSA. In the unadjusted analyses, participants with OSA on average showed thinner peripapillary RNFL at the inferotemporal (P = 0.026) and superotemporal (P = 0.008) segments compared with those without OSA. Additionally, higher AHI results were associated with thinner RNFL superotemporally (P = 0.007). These findings remained significant after adjusting for gender, body mass index, ethnicity, and potential ocular confounders. There were no significant differences in optic disc measures between groups of OSA severity. Obstructive sleep apnea may be associated with preclinical thinning of the peripapillary RNFL in young adults. This suggests that an increased glaucoma risk already may be present in individuals with OSA since young adulthood. Long-term follow-up of this cohort will allow further optic disc changes in relationship to polysomnography parameters to be documented and associations with future glaucoma diagnosis to be explored.


Blocking TLR7- and TLR9-mediated IFN-α production by plasmacytoid dendritic cells does not diminish immune activation in early SIV infection.
Persistent production of type I interferon (IFN) by activated plasmacytoid dendritic cells (pDC) is a leading model to explain chronic immune activation in human immunodeficiency virus (HIV) infection but direct evidence for this is lacking. We used a dual antagonist of Toll-like receptor (TLR) 7 and TLR9 to selectively inhibit responses of pDC but not other mononuclear phagocytes to viral RNA prior to and for 8 weeks following pathogenic simian immunodeficiency virus (SIV) infection of rhesus macaques. We show that pDC are major but not exclusive producers of IFN-α that rapidly become unresponsive to virus stimulation following SIV infection, whereas myeloid DC gain the capacity to produce IFN-α, albeit at low levels. pDC mediate a marked but transient IFN-α response in lymph nodes during the acute phase that is blocked by administration of TLR7 and TLR9 antagonist without impacting pDC recruitment. TLR7 and TLR9 blockade did not impact virus load or the acute IFN-α response in plasma and had minimal effect on expression of IFN-stimulated genes in both blood and lymph node. TLR7 and TLR9 blockade did not prevent activation of memory CD4+ and CD8+ T cells in blood or lymph node but led to significant increases in proliferation of both subsets in blood following SIV infection. Our findings reveal that virus-mediated activation of pDC through TLR7 and TLR9 contributes to substantial but transient IFN-α production following pathogenic SIV infection. However, the data indicate that pDC activation and IFN-α production are unlikely to be major factors in driving immune activation in early infection. Based on these findings therapeutic strategies aimed at blocking pDC function and IFN-α production may not reduce HIV-associated immunopathology.


Comparative study between paracetamol and two different doses of pregabalin on postoperative pain in laparoscopic cholecystectomy.
Postoperative pain is the primary reason for prolonged hospital stay after laparoscopic cholecystectomy. This study compared the effect of a single oral preoperative administration of paracetamol (1 g) with 2 different doses of pregabalin (150 or 300 mg) for attenuating postoperative pain and analgesic consumption. Seventy-five patients, aged 18-60 years, American Society of Anesthesiologists' physical status I and II undergoing elective laparoscopic cholecystectomy were included in this randomized controlled study. Patients were divided into three groups, 25 each to receive either oral paracetamol 1 g (group I, control group) or pregabalin 150 (group II) or 300 mg (group III), 2 h before surgery. Postoperative pain was evaluated based on visual analog scale over a period of 6 h and 1(st) time for rescue analgesia. Postoperative sedation, hemodynamic changes, serum cortisol level, and side effects were also evaluated. There was a significant decrease in mean heart rate, mean systolic blood pressure, sedation score, pain score, and delayed the first request for analgesics postoperatively in group (II) and group (III) compared to group (I) 2 h postoperatively. There was no significant difference in group (III) compared to group (II) postoperatively. The incidence of postoperative side effects was more in group (III). The single oral preoperative dose administration of pregabalin had significant opioid-sparing effect in the first 6 h after surgery, whereas side effects were more common with administration of pregabalin 300 mg.


DNA barcoding reveals limited accuracy of identifications based on folk taxonomy.
The trade of plant roots as traditional medicine is an important source of income for many people around the world. Destructive harvesting practices threaten the existence of some plant species. Harvesters of medicinal roots identify the collected species according to their own folk taxonomies, but once the dried or powdered roots enter the chain of commercialization, accurate identification becomes more challenging. A survey of morphological diversity among four root products traded in the medina of Marrakech was conducted. Fifty-one root samples were selected for molecular identification using DNA barcoding using three markers, trnH-psbA, rpoC1, and ITS. Sequences were searched using BLAST against a tailored reference database of Moroccan medicinal plants and their closest relatives submitted to NCBI GenBank. Combining psbA-trnH, rpoC1, and ITS allowed the majority of the market samples to be identified to species level. Few of the species level barcoding identifications matched the scientific names given in the literature, including the most authoritative and widely cited pharmacopeia. The four root complexes selected from the medicinal plant products traded in Marrakech all comprise more than one species, but not those previously asserted. The findings have major implications for the monitoring of trade in endangered plant species as morphology-based species identifications alone may not be accurate. As a result, trade in certain species may be overestimated, whereas the commercialization of other species may not be recorded at all.


Management of Hereditary Spastic Paraplegia: A Systematic Review of the Literature.
The term hereditary spastic paraplegia (HSP) embraces a clinically and genetically heterogeneous group of neurodegenerative diseases characterized by progressive spasticity and weakness of the lower limbs. There currently exist no specific therapies for HSP, and treatment is exclusively symptomatic, aimed at reducing muscle spasticity, and improving strength and gait. The authors set out to perform a comprehensive systematic review of the available scientific literature on the treatment of HSP, applying Cochrane Collaboration methods. The Google Scholar, PubMed and Scopus electronic databases were searched to find relevant randomized control trials (RCTs) and open-label interventional studies, prospective, and retrospective observational studies of supplements, medications, and physical therapy, as well as case reports and case series. Two authors independently analyzed 27 articles selected on the basis of a series of inclusion criteria. Applying a best-evidence synthesis approach, they evaluated these articles for methodological quality. A standardized scoring system was used to obtain interrater assessments. Disagreements were resolved by discussion. The 27 articles focused on pharmacological treatment (n = 17 articles), physical therapy (n = 5), surgical treatment (n = 5). The drugs used in the 17 articles on pharmacological therapy were: gabapentin, progabide, dalfampridine, botulinum toxin, L-Dopa, cholesterol-lowering drugs, betaine, and folinic acid. Gabapentin, progabide, dalfampridine, and botulinum toxin were used as antispastic agents; the study evaluating gabapentin efficacy was well-designed, but failed to demonstrate any significant improvement. L-Dopa, cholesterol-lowering drugs, betaine, and folinic acid were only used in specific HSP subtypes. Two of the three studies evaluating cholesterol-lowering drugs (in SPG5 patients) were well-designed and showed a significant reduction of specific serum biomarkers (oxysterols), but clinical outcomes were not evaluated. The articles focusing on physical treatment and surgical therapy were found to be of low/medium quality and, accordingly, failed to clarify the role of these approaches in HSP. Despite recent advances in understanding of the pathogenesis of HSP and the possibility, in several centers, of obtaining more precise and rapid molecular diagnoses, there is still no adequate evidence base for recommending the various published therapies. Well-designed RCTs are needed to evaluate the efficacy of both symptomatic and pathogenetic treatments.


Improvements in an in vivo neutron activation analysis (NAA) method for the measurement of fluorine in human bone.
We previously published a method for the in vivo measurement of bone fluoride using neutron activation analysis (NAA) and demonstrated the utility of the technique in a pilot study of environmentally exposed people. The method involved activation of the hand in an irradiation cavity at the McMaster University Accelerator Laboratory and acquisition of the resultant γ-ray signals in a '4π' NaI(Tl) detector array of nine detectors. In this paper we describe a series of improvements to the method. This was investigated via measurement of hand simulating phantoms doped with varying levels of fluorine and fixed amounts of sodium, chlorine and calcium. Four improvements to the technique were tested since our first publication. The previously published detection limit for phantom measurements using this system was 0.66 mg F/g Ca. The accelerator irradiation and detection facilities were relocated to a new section of the laboratory and one more detector was added to the detection system. This was found to reduce the detection limit (possibly because of better detection shielding and additional detector) to 0.59 mg F/g Ca, a factor of 1.12. A new set of phantoms was developed and in this work we show that they improved the minimum detectable limit for fluoride in phantoms irradiated using neutrons produced by 2.15 MeV protons on lithium by a factor of 1.55. We compared the detection limits previously obtained using a summed signal from the nine detectors with the detection limit obtained by acquiring the spectra in anticoincidence mode for reduction of the disturbing signal from chlorine in bone. This was found to improve the ratio of the detection of fluorine to chlorine (an interfering signal) by a factor of 2.8 and the resultant minimum detection limit was found to be reduced by a factor of 1.2. We studied the effects of changing the timing of γ-ray acquisition. Our previously published data used a series of three 10 s acquisitions followed by a 300 s count. Changing the acquisition to a series of six 5 s acquisitions was found to further improve the detection limit by a factor of 1.4. We also present data showing that if the neutron dose is delivered to the phantom in a shorter time period, i.e. the dose rate is increased and irradiation shortened then the detection limit can be reduced by a further factor of 1.35.The overall improvement in detection limit by employing all of these changes was found to be a factor of 3.9. The technique now has an in phantom detection limit of 0.17 mg F/g Ca compared to a previous detection limit of 0.66 mg F/g Ca. The system can now be tested on human volunteers to see if individuals with diagnosed fluorosis can be distinguished from the general Canadian population using this technique.


Glyoxalase 1 overexpression does not affect atherosclerotic lesion size and severity in ApoE-/- mice with or without diabetes.
Advanced glycation end-products (AGEs) and their precursors have been associated with the development of atherosclerosis. We recently discovered that glyoxalase 1 (GLO1), the major detoxifying enzyme for AGE precursors, is decreased in ruptured human plaques, and that levels of AGEs are higher in rupture-prone plaques. We here investigated whether overexpression of human GLO1 in ApoE(-/-) mice could reduce the development of atherosclerosis. We crossed C57BL/6 ApoE(-/-) mice with C57BL/6 GLO1 overexpressing mice (huGLO1(+/-)) to generate ApoE(-/-) (n = 16) and ApoE(-/-) huGLO1(+/-) (n = 20) mice. To induce diabetes, we injected a subset with streptozotocin (STZ) to generate diabetic ApoE(-/-) (n = 8) and ApoE(-/-) huGLO1(+/-) (n = 13) mice. All mice were fed chow and sacrificed at 25 weeks of age. The GLO1 activity was three-fold increased in huGLO1(+/-) aorta, but aortic root lesion size and phenotype did not differ between mice with and without huGLO1(+/-) overexpression. We detected no differences in gene expression in aortic arches, in AGE levels and cytokines, in circulating cells, and endothelial function between ApoE(-/-) mice with and without huGLO1(+/-) overexpression. Although diabetic mice showed decreased GLO1 expression (P < 0.05) and increased lesion size (P < 0.05) in comparison with non-diabetic mice, GLO1 overexpression also did not affect the aortic root lesion size or inflammation in diabetic mice. In ApoE(-/-) mice with or without diabetes, GLO1 overexpression did not lead to decreased atherosclerotic lesion size or systemic inflammation. Increasing GLO1 levels does not seem to be an effective strategy to reduce glycation in atherosclerotic lesions, likely due to increased AGE formation through GLO1-independent mechanisms.


A directional remote-microphone for bimodal cochlear implant recipients.
To evaluate whether speech recognition in noise differs according to whether a wireless remote microphone is connected to just the cochlear implant (CI) or to both the CI and to the hearing aid (HA) in bimodal CI users. The second aim was to evaluate the additional benefit of the directional microphone mode compared with the omnidirectional microphone mode of the wireless microphone. This prospective study measured Speech Recognition Thresholds (SRT) in babble noise in a 'within-subjects repeated measures design' for different listening conditions. Eighteen postlingually deafened adult bimodal CI users. No difference in speech recognition in noise in the bimodal listening condition was found between the wireless microphone connected to the CI only and to both the CI and the HA. An improvement of 4.1 dB was found for switching from the omnidirectional microphone mode to the directional mode in the CI only condition. The use of a wireless microphone improved speech recognition in noise for bimodal CI users. The use of the directional microphone mode led to a substantial additional improvement of speech perception in noise for situations with one target signal.


Global genomic diversity of Oryza sativa varieties revealed by comparative physical mapping.
Bacterial artificial chromosome (BAC) physical maps embedding a large number of BAC end sequences (BESs) were generated for Oryza sativa ssp. indica varieties Minghui 63 (MH63) and Zhenshan 97 (ZS97) and were compared with the genome sequences of O. sativa spp. japonica cv. Nipponbare and O. sativa ssp. indica cv. 93-11. The comparisons exhibited substantial diversities in terms of large structural variations and small substitutions and indels. Genome-wide BAC-sized and contig-sized structural variations were detected, and the shared variations were analyzed. In the expansion regions of the Nipponbare reference sequence, in comparison to the MH63 and ZS97 physical maps, as well as to the previously constructed 93-11 physical map, the amounts and types of the repeat contents, and the outputs of gene ontology analysis, were significantly different from those of the whole genome. Using the physical maps of four wild Oryza species from OMAP (http://www.omap.org) as a control, we detected many conserved and divergent regions related to the evolution process of O. sativa. Between the BESs of MH63 and ZS97 and the two reference sequences, a total of 1532 polymorphic simple sequence repeats (SSRs), 71,383 SNPs, 1767 multiple nucleotide polymorphisms, 6340 insertions, and 9137 deletions were identified. This study provides independent whole-genome resources for intra- and intersubspecies comparisons and functional genomics studies in O. sativa. Both the comparative physical maps and the GBrowse, which integrated the QTL and molecular markers from GRAMENE (http://www.gramene.org) with our physical maps and analysis results, are open to the public through our Web site (http://gresource.hzau.edu.cn/resource/resource.html).


Structure and temporal dynamics of populations within wheat streak mosaic virus isolates.
Variation within the Type and Sidney 81 strains of wheat streak mosaic virus was assessed by single-strand conformation polymorphism (SSCP) analysis and confirmed by nucleotide sequencing. Limiting-dilution subisolates (LDSIs) of each strain were evaluated for polymorphism in the P1, P3, NIa, and CP cistrons. Different SSCP patterns among LDSIs of a strain were associated with single-nucleotide substitutions. Sidney 81 LDSI-S10 was used as founding inoculum to establish three lineages each in wheat, corn, and barley. The P1, HC-Pro, P3, CI, NIa, NIb, and CP cistrons of LDSI-S10 and each lineage at passages 1, 3, 6, and 9 were evaluated for polymorphism. By passage 9, each lineage differed in consensus sequence from LDSI-S10. The majority of substitutions occurred within NIa and CP, although at least one change occurred in each cistron except HC-Pro and P3. Most consensus sequence changes among lineages were independent, with substitutions accumulating over time. However, LDSI-S10 bore a variant nucleotide (G(6016)) in NIa that was restored to A(6016) in eight of nine lineages by passage 6. This near-global reversion is most easily explained by selection. Examination of nonconsensus variation revealed a pool of unique substitutions (singletons) that remained constant in frequency during passage, regardless of the host species examined. These results suggest that mutations arising by viral polymerase error are generated at a constant rate but that most newly generated mutants are sequestered in virions and do not serve as replication templates. Thus, a substantial fraction of variation generated is static and has yet to be tested for relative fitness. In contrast, nonsingleton variation increased upon passage, suggesting that some mutants do serve as replication templates and may become established in a population. Replicated mutants may or may not rise to prominence to become the consensus sequence in a lineage, with the fate of any particular mutant subject to selection and stochastic processes such as genetic drift and population growth factors.


A Prospective Cohort Study on Injuries Among Intensely Physically Active High School Students.
The leading cause of nonfatal injuries in age group 14-19 is sports injuries. Purpose of the study was to determine the association between intense physical activity and injury and to identify the circumstances and environment in which injuries are most likely to occur. A prospective cohort study included 698 high school students 15-19 years old, divided into those exposed and those unexposed to intense physical activity. The international standard questionnaire about physical activity (International Physical Activity Questionnaire-IPAQ) and the metabolic equivalent task (MET) scores were used. The risk of injuries was 7 times higher (relative risk [RR]: 7.041; 95% confidence interval [CI]: 6.071, 8.187) and the risk of injuries requiring treatment in health facilities was 15 times higher (RR: 14.717; 95% CI: 10.652, 20.592) in the intensely physically active adolescents. The risk of gaining sports injuries was 11 times higher in the exposed group (RR: 11.212; 95% CI: 9.013, 14.074), with a significantly higher incidence rate (Inc.) among men (82.9 per 100). Most injuries occurred in football (Inc. 4.4 per 1000 hours), volleyball (Inc. 3.9 per 1000 hours), and boxing/kickboxing (Inc. 3.7 per 1000 hours). Intensely physically active high school students have a much higher risk of injury, which usually occurs during training or a match.


More than just an eyesore: local insights and solutions on vacant land and urban health.
Vacant land is a significant economic problem for many cities, but also may affect the health and safety of residents. In order for community-based solutions to vacant land to be accepted by target populations, community members should be engaged in identifying local health impacts and generating solutions. We conducted 50 in-depth semi-structured interviews with people living in Philadelphia, Pennsylvania, a city with high vacancy, about the impact of vacant land on community and individual health and safety, as well as ideas for solutions to vacant land. Participants described a neighborhood physical environment dominated by decaying abandoned homes and overgrown vacant lots which affected community well-being, physical health, and mental health. Vacant land was thought to affect community well-being by overshadowing positive aspects of the community, contributing to fractures between neighbors, attracting crime, and making residents fearful. Vacant land was described as impacting physical health through injury, the buildup of trash, and attraction of rodents, as well as mental health through anxiety and stigma. Participants had several ideas for solutions to vacant land in their community, including transformation of vacant lots into small park spaces for the elderly and playgrounds for youth, and the use of abandoned homes for subsidized housing and homeless shelters. A few participants took pride in maintaining vacant lots on their block, and others expressed interest in performing maintenance but lacked the resources to do so. Public health researchers and practitioners, and urban planners should engage local residents in the design and implementation of vacant land strategies. Furthermore, municipalities should ensure that the health and safety impact of vacant land helps drive policy decisions around vacant land.


A prospective study of the utility of plasma biomarkers to diagnose alcoholic hepatitis.
The diagnosis of alcoholic hepatitis (AH) often requires a transjugular liver biopsy (TJLB), a procedure that is not always readily accessible. We analyzed plasma biomarkers to estimate the presence of histological features of AH among patients with clinical suspicion of AH. Using enzyme-linked immunosorbent assay, we tested M65 and M30 (circulating fragments of cytokeratin-18) and their respective fraction carried by microvesicles (MVs), CCL20 and TREM1. Leukocyte, platelet, and endothelial-derived MVs were quantified by way of flow cytometry. Test and validation cohorts prospectively included patients with clinical features of AH undergoing TJLB. In the test cohort, 46 of 83 (55%) patients showed histological features of AH. Age, bilirubin, INR, and creatinine (ABIC) score was B or C in 83%. Patients with histologically proven AH had higher levels of total and MV-bound M65 and total and MV-bound M30 and CCL20 than those without (P < 0.001 for all tests). Levels of TREM-1 and of subpopulations of MVs were not different between groups. M65 and M30 both had an area under the receiver operating characteristics curve of 0.84 to estimate the presence of AH. For M65, a cutoff of 2000 IU/L had a positive predictive value of 91%, whereas a cutoff of 641 IU/L had a negative predictive value of 88%. In the validation cohort, AH was histologically confirmed in 48 of 68 (71%) patients. ABIC score was B or C in 69% of patients. For M65, the above cutoffs had a diagnostic accuracy of 81%. Even better results were obtained in patients with suspicion of severe AH (ABIC B or C) in both cohorts. Plasma levels of cytokeratin-18 fragments are reliable noninvasive markers of AH. Using the proposed cutoffs for M65, two thirds of TJLB can be avoided, which can be useful in centers where this technique is not readily available. (Hepatology 2017;66:555-563).


Design and analysis of wearable pupillometer for autonomic neuropathy of diabetic patients.
Diabetes is a familiar disease in modern society. In the early stage of diabetes, symptoms are unobvious, but they usually induce diabetic autonomic neuropathy or, worse, cardiovascular autonomic neuropathy. Pupillometers are effective instruments for observing human pupils. This article presents a novel wearable pupillometer design, without external light artifacts, and an embedded algorithm with blinking elimination, which investigates autonomic neuropathy through recording pupil dynamics triggered by an external sensitive invisible light source. The pupillometer is experimented on 36 healthy subjects and 10 diabetic patients under four different colors (white, red, green, and blue) as well as two different light intensities: 50 and 500 mcd. Ten parameters derived from pupil diameter, pupil response time, and pupil response speed will be evaluated for the healthy subjects and diabetic patients. The results show that three in four parameters related to pupil diameters, one in four related to light intensities, and one in two related to pupil response speed could have significant differences (p<0.05) between healthy subjects and diabetic patients. These parameters obtain over 85% sensitivity, 83% specificity, and 88% accuracy. The pupillometer is proven reliable, effective, portable, and inexpensive for diagnosing diabetes in an early stage.


A description of two new species of the genus Erenna (Siphonophora: Physonectae: Erennidae), with notes on recently collected specimens of other Erenna species.
Two new Erenna species, E. insidiator sp. nov. and E. sirena sp. nov., are described from specimens collected in the vicinity of Monterey Bay, California, and also, for E. sirena at the southern end of the Gulf of California, Mexico. Further information on the three extant Erenna species is given, based on specimens collected in the same areas. These have enabled, for instance, the identification of three types of tentilla on the tentacles of E. cornuta Pugh, 2001, rather than the two noted on the single previously known specimen. The genus is remarkable for the presence of bioluminescent lures on the tentilla of all five species. In E. sirena sp. nov. the tentilla are also covered by a red-fluorescent layer, which was briefly described by Haddock et al. (2005), and further details are given herein. Another extraordinary feature of the colonies E. sirena sp. nov. is that the main part of the tentacle, with its tentilla, can be extended away from the siphosomal stem on a long peduncle. This phenomenon also appears to occur in E. laciniata Pugh, 2001, and has not been observed before for other physonect species.


[Effect of liver X receptor agonist T0901317 on endothelin-1 induced murine HL-1 cardiomyocytes hypertrophy].
To investigate the role of liver X receptors (LXRs) on endothelin-1 (ET-1) induced murine HL-1 cardiomyocytes hypertrophy. Cultured murine HL-1 cardiomyocytes were divided into four experiment groups: (1) CONTROL GROUP:treated with DMSO; (2) T0901317 group:treated with LXRs agonist T0901317 (1 µmol/L); (3) ET-1 group:treated with ET-1 (1 nmol/L); (4) T0901317 + ET-1 group:treated with T0901317 (1 µmol/L) for 8 hours, then treated with ET-1 (1 nmol/L). Twenty-four hours later, immunofluorescent staining was performed on HL-1 cells, the surface area of HL-1 cells was analyzed with NIH Image J software, and the synthetic rate of protein in HL-1 cells was detected by (3)H-leucine incorporation. The mRNA level of atrial natriuretic peptide (ANP) and β-myosin heavy chain (β-MyHC) was measured by quantitative realtime PCR. The effect of T0901317 on mRNA expression of ANP was also detected after LXRs gene silencing. The surface area of HL-1 cells, mRNA expression of ANP and β-MyHC, and (3)H-leucine incorporation in ET-1 group were 2.00 ± 0.29, 1.98 ± 0.47, 2.13 ± 0.39 and 1.79 ± 0.17, respectively, which were significantly higher than those of control group (1.00 ± 0.26, 1.00 ± 0.21, 1.00 ± 0.31 and 1.00 ± 0.03, respectively, all P < 0.05). Compared with ET-1 group, the surface area of HL-1 cells, mRNA expression of ANP and β-MyHC, and (3)H-leucine incorporation were significantly decreased in T0901317 + ET-1 group (1.24 ± 0.25, 1.19 ± 0.21, 1.48 ± 0.27 and 1.15 ± 0.11, respectively, all P < 0.05). After inhibition of LXRα/β expression in HL-1 cardiomyocytes using the specific siRNAs, the mRNA expression of ANP in T0901317 + ET-1 group was 1.78 ± 0.05, which was similar as that in ET-1 group (1.94 ± 0.17, P > 0.05). T0901317, an agonist of LXRs, could inhibit ET-1 induced cardiac hypertrophy in vitro, and LXR ligand-mediated inhibition on ANP mRNA expression by T0901317 is receptor dependent.


Report of the Cent Gardes HIV Vaccine Conference: The B-cell Response to HIV. Part 1: Broadly Neutralizing Antibodies Fondation Mérieux Conference Center, Veyrier du Lac, France, 5-7 November 2012.
The Cent Gardes Conference on HIV Vaccines took place on November 5-7, 2012 at the Fondation Mérieux Conference Center, Annecy, France. The aim of the meeting was to review the B cell response to human immunodeficiency virus-1 (HIV-1) infection and immunization, from broadly neutralizing antibodies (bnAbs) to non-neutralizing antibodies (n-nAbs). The production of cross-reactive bnAbs is one of the greatest challenges in HIV-1 vaccine development. In natural HIV infection, bnAbs are observed in only a minority of infected individuals and take a few years to develop. This report presents a comprehensive review of how these Abs arise, the possible role of viral evolution, and the activation and maturation requirements of B cell lines that lead to their production. Passive immunization with bnAbs provides efficient, cross-clade protection against simian/human immunodeficiency chimeric virus (SHIV) challenges in nonhuman primates. Despite many efforts to design immunogens that elicit them by active immunization, no immunogen other than HIV itself has yet been able to elicit a bnAb response. For this reason, innovative approaches are under investigation, including their production in the body through a gene delivery approach, vector immunoprophylaxis.


Mountain pygmies of Western New Guinea: a morphological and molecular approach.
The presence of "pygmy" or pygmoid groups among New Guinea populations has been the object of scientific interest since the end of the nineteenth century. Morphological and molecular data are used here to study western New Guinea population variability, focusing in particular on two pygmoid groups living in the eastern fringe highlands of Papua: the Una and the Ketengban. Various kinds of anthropometric data are examined, as well as height, weight, and body mass index, to carry out comparisons with nearby ethnic groups living in the highland and lowland regions. The Ketengban data were also compared with other data recorded 20 years before. The results of previous research on the sequencing of the mitochondrial DNA hypervariable segment 1 region and nuclear DNA nonrecombining Y-chromosome polymorphisms are presented. Both morphological and molecular studies involve adult subjects of both genders, representative of the same ethnic groups and/or geographic regions. The pygmoid groups turn out to be significantly different from all other study groups, due to their small size, as confirmed by analysis of variance, although significant height and weight increments are observed with respect to those previously recorded. However, putative neutral genetic variation estimated from mitochondrial DNA and Y-chromosome markers support a recent shared common history between these pygmoid populations and the other central Papua groups (except for the Dani-Lani). These findings suggest that the short-stature phenotype is an independent secondary adaptation, possibly driven by an iodine-deficient environment, which leaves the potential for further investigations.


Spontaneous spheroid budding from monolayers: a potential contribution to ovarian cancer dissemination.
Ovarian cancer is the most lethal gynaecologic cancer, in large part because of its early dissemination and rapid development of chemotherapy resistance. Spheroids are clusters of tumor cells found in the peritoneal fluid of patients that are thought to promote this dissemination. Current models suggest that spheroids form by aggregation of single tumor cells shed from the primary tumor. Here, we demonstrate that spheroids can also form by budding directly as adherent clusters from a monolayer. Formation of budded spheroids correlated with expression of vimentin and lack of cortical E-cadherin. We also found that compared to cells grown in monolayers, cells grown as spheroids acquired progressive resistance to the chemotherapy drugs Paclitaxel and Cisplatin. This resistance could be completely reversed by dissociating the spheroids. Our observations highlight a previously unappreciated mode of spheroid formation that might have implications for tumor dissemination and chemotherapy resistance in patients, and suggest that this resistance might be reversed by spheroid dissociation.


CRB1-Associated Retinal Dystrophies: A Prospective Natural History Study in Anticipation of Future Clinical Trials.
To investigate the natural disease course of retinal dystrophies associated with crumbs cell polarity complex component 1 (CRB1) and identify clinical end points for future clinical trials. Single-center, prospective case series. An investigator-initiated nationwide collaborative study that included 22 patients with CRB1-associated retinal dystrophies. Patients underwent ophthalmic assessment at baseline and 2 years after baseline. Clinical examination included best-corrected visual acuity (BCVA) using Early Treatment Diabetic Retinopathy Study charts, Goldmann kinetic perimetry (V4e isopter seeing retinal areas), microperimetry, full-field electroretinography, full-field stimulus threshold (FST), fundus photography, spectral-domain optical coherence tomography, and fundus autofluorescence imaging. Based on genetic, clinical, and electrophysiological data, patients were diagnosed with retinitis pigmentosa (19 [86%]), cone-rod dystrophy (2 [9%]), or isolated macular dystrophy (1 [5%]). Analysis of the entire cohort at 2 years showed no significant changes in BCVA (P = .069) or V4e isopter seeing retinal areas (P = .616), although signs of clinical progression were present in individual patients. Macular sensitivity measured on microperimetry revealed a significant reduction at the 2-year follow-up (P < .001). FST responses were measurable in patients with nonrecordable electroretinograms. On average, FST responses remained stable during follow-up. In CRB1-associated retinal dystrophies, visual acuity and visual field measures remain relatively stable over the course of 2 years. Microperimetry showed a significant decrease in retinal sensitivity during follow-up and may be a more sensitive progression marker. Retinal sensitivity on microperimetry may serve as a functional clinical end point in future human treatment trials for CRB1-associated retinal dystrophies.


Lower endogenous androgens predict central adiposity in men.
Central adiposity, sometimes described as male pattern fat distribution, is adversely related to cardiovascular risk and mortality independent of other measures of obesity. In a cohort of 511 men aged 30 to 79 years in 1972 to 1974, levels of androstenedione, testosterone, and sex hormone-binding globulin measured at baseline were inversely related to subsequent central adiposity, estimated 12 years later using the waist-hip circumference ratio. The observed differences in waist-hip ratio between top and bottom tertiles of these hormones and sex hormone-binding globulin were similar to mean waist-hip ratio differences between men with stroke or ischemic heart disease and those without in another prospective study. These findings, consistent with studies suggesting that testosterone seems to mobilize the abdominal depot on males, suggest that "male pattern" fat distribution may be a misleading description for central adiposity, at least, in men. Degree of maleness as indicated by total androgen levels is, in fact, negatively associated with central adiposity. However, the role of sex hormone-binding globulin in regulating androgenic activity warrants further investigation.


Health-related quality of life in children after burn injuries: A systematic review.
Through improved survival of burns, more children have to deal with consequences of burns. Health-related quality of life (HRQL) measurement is important to qualify the perceived burden of burns in children. No systematic study of this outcome in children exists. Therefore, our objective was to review study designs, instruments, methodological quality, outcomes, and predictors of HRQL in children after burns. A systematic literature search was conducted in CINAHL, Embase, Google Scholar, Medline, The Cochrane library, and Web of science (PROSPERO ID, CRD42016048065). Studies examining HRQL in pediatric burn patients were included. The risk of bias was assessed using the Quality in Prognostic Studies (QUIPS) tool. Twenty-seven studies using 12 HRQL instruments were included. The Burns Outcome Questionnaire aged 0 to 4 and 5 to 18 years were most often applied. All longitudinal studies showed improvement of HRQL over time. However, problems were reported on the longer term on the domains "(parental) concern" and "appearance." Parental proxy scores were in general comparable to children's self-ratings. Severity of burns, facial burns, hand burns, comorbidity, and short time since burn predicted an impaired HRQL. The risk of bias of the studies was, in general, moderate. Health-related quality of life in children after burns increases over time. Domains and patient groups that require special attention are identified. However, due to lack of comparability of studies, the available information could not be used optimally. To further improve our understanding of HRQL, consensus on design, data-analysis, and data presentation are needed. Systematic review, level III.


A systematic review of the clinical effectiveness and cost-effectiveness and economic modelling of minimal incision total hip replacement approaches in the management of arthritic disease of the hip.
To assess the clinical effectiveness and cost-effectiveness of minimal incision approaches to total hip replacement (THR) for arthritis of the hip. Major electronic databases were searched from 1966 to 2007. Relevant websites were also examined and experts in the field were consulted. Studies of minimal (one or two) incision THR compared with standard THR were assessed for inclusion in the review of clinical effectiveness. A systematic review of economic evaluations comparing a minimal incision approach to standard THR was also performed and the estimates from the systematic review of clinical effectiveness were incorporated into an economic model. Utilities data were sourced to estimate quality-adjusted life-years (QALYs). Due to lack of data, no economic analysis was conducted for the two mini-incision surgical method. Nine randomised controlled trials (RCTs), 17 non-randomised comparative studies, six case series and one registry were found to be useful for the comparison of single mini-incision THR with standard THR. One RCT compared two mini-incision THR with standard THR, and two RCTs, five non-randomised comparative studies and two case series compared two mini-incision with single mini-incision THR. The RCTs were of moderate quality. Most had fewer than 200 patients and had a follow-up period of less than 1 year. The single mini-incision THR may have some perioperative advantages, e.g. blood loss [weighted mean difference (WMD) -57.71 ml, p<0.01] and shorter operative time, of uncertain practical significance. It may also offer a shorter recovery period and greater patient satisfaction. Evidence on long-term outcomes (especially revision) is too limited to be useful. Lack of data prevented subgroup analysis. With respect to the two-incision approach, data were suggestive of shorter recovery compared with single-incision THR, but conclusions must be treated with caution. The costs to the health service, per patient, of single mini-incision THR depend upon assumptions made, but are similar at one year (7060 pounds sterling vs 7350 pounds sterling for standard THR). For a 40-year time horizon the costs were 11,618 pounds sterling for mini-incision and 11,899 pounds sterling for standard THR. Two existing economic evaluations were identified, but they added little, if any, value to the current evidence base owing to their limited quality. In the economic model, mini-incision THR was less costly and provided slightly more QALYs in both the 1- and 40-year analyses. The mean QALYs at 1 year were 0.677 for standard THR and 0.695 for mini-incision THR. At 40 years, the mean QALYs were 8.463 for standard THR and 8.480 for mini-incision. At 1 year the probabilistic sensitivity analyses indicate that mini-incision THR has a 95% probability of being cost-effective if society's willingness to pay for a QALY were up to 50,000 pounds sterling. This is reduced to approximately 55% for the 40-year analysis. The results were driven by the assumption of a 1-month earlier return to usual activities and a decreased hospital length of stay and operation duration following mini-incision THR. If mini-incision THR actually required more intensive use of resources it would become approximately 200 pounds sterling more expensive and would only be cost-effective (cost per QALY>30,000 pounds sterling) if recovery was 1.5 weeks faster. A threshold analysis around risk of revision showed, using the same cost per QALY threshold, mini-incision THR would have to have no more than a 7.5% increase in revisions compared with standard THR for it to be no longer considered cost-effective (one more revision for every 200 procedures performed). Further sensitivity analysis involved relaxing assumptions of equal long-term outcomes where possible. and broadly similar results to the base-case analysis were found in this and further sensitivity analyses. Compared with standard THR, minimal incision THR has small perioperative advantages in terms of blood loss and operation time. It may offer a shorter hospital stay and quicker recovery. It appears to have a similar procedure cost to standard THR, but evidence on its longer term performance is very limited. Further long-term follow-up data on costs and outcomes including analysis of subgroups of interest to the NHS would strengthen the current economic evaluation.


The effect of gene duplication on homology.
Genes related by gene duplication within an organism's evolutionary lineage are termed paralogues; genes related by speciation are orthologues. It is generally agreed that orthologous genes must be compared when using DNA sequences to reconstruct the evolutionary history of organisms. There is an important exception: information from paralogous genes can reveal the root position of a phylogenetic tree. The duplicated rDNA genes of arrow worms provide an example. Gene duplication is also relevant when comparing gene expression between taxa; for example, when trying to identify homologous roles of genes. When gene duplication occurred after lineage divergence, single orthologues no longer exist, and comparison is complicated. This is a particular problem when comparing roles of vertebrate and invertebrate genes. Amphioxus and ascidian genes can be useful in such situations, since they diverged before extensive gene duplication in the vertebrate lineage. Using Otx and Pax as examples, I show how examination of amphioxus or ascidian genes reveals patterns of gene divergence after duplication, assisting the identification of homologous gene functions. Given the problems of comparing duplicated genes between species, the time is ripe for the introduction of additional terminology to elaborate on the concepts of paralogy and orthology.


Cancer recurrence: an important but missing variable in national cancer registries.
Cancer recurrence is a critically important outcome to patients and providers. However, no publicly available cancer registry data contain recurrence information. The National Cancer Data Base (NCDB) collects recurrence data; however, this information is not provided to researchers because of completeness and accuracy concerns. Our objective was to examine completeness of cancer recurrence information in the NCDB. Stage I-III thyroid/colon/melanoma/pancreas/breast cancers diagnosed in 2002-2005 were identified. Recurrence status, recurrence type, and recurrence date were evaluated for data completeness. Patient, tumor, and hospital factors were examined using generalized linear mixed models. Pseudo-R (2) statistics estimated the relative contribution of patient and hospital factors. Of 702,144 patients with thyroid/colon/melanoma/pancreas/breast cancers treated in 1405 hospitals, recurrence information was incomplete in 21.5/24.0/20.2/34.8/18.2 % of patients, respectively. On average, hospitals had incomplete recurrence information on 56.7-66.7 % of their patients. Patients with incomplete information had more comorbidities, a higher cancer stage, non-private insurance, and lived farther from the hospital. Hospitals with the poorest collection were larger tertiary hospitals serving higher-income patients. However, these patients and hospital factors explained less than 3 %, while unexplained hospital variation accounted for the largest part of the observed variation (%ΔR (2) = 84 %). The majority of hospitals report incomplete recurrence information for more than half of their patients. The presence of incomplete recurrence information was largely dependent on undefined hospital factors, rather than patient or tumor characteristics. Attempts to improve cancer recurrence information should focus on hospital operational and process factors surrounding how the hospital tumor registries collect recurrence data.


Mutations in copper-zinc superoxide dismutase that cause amyotrophic lateral sclerosis alter the zinc binding site and the redox behavior of the protein.
A series of mutant human and yeast copper-zinc superoxide dismutases has been prepared, with mutations corresponding to those found in familial amyotrophic lateral sclerosis (ALS; also known as Lou Gehrig's disease). These proteins have been characterized with respect to their metal-binding characteristics and their redox reactivities. Replacement of Zn2+ ion in the zinc sites of several of these proteins with either Cu2+ or Co2+ gave metal-substituted derivatives with spectroscopic properties different from those of the analogous derivative of the wild-type proteins, indicating that the geometries of binding of these metal ions to the zinc site were affected by the mutations. Several of the ALS-associated mutant copper-zinc superoxide dismutases were also found to be reduced by ascorbate at significantly greater rate than the wild-type proteins. We conclude that similar alterations in the properties of the zinc binding site can be caused by mutations scattered throughout the protein structure. This finding may help to explain what is perhaps the most perplexing question in copper-zinc superoxide dismutase-associated familial ALS-i.e., how such a diverse set of mutations can result in the same gain of function that causes the disease.


Differences in the justification of choices in moral dilemmas: effects of gender, time pressure and dilemma seriousness.
The effects on moral reasoning of gender, time pressure and seriousness of the issue at hand were investigated. In Experiment 1, 72 university students were presented with moral dilemmas and asked what actions the actors involved should take and to justify this. Women were found to be more care-oriented in their reasoning than men, supporting Gilligan's moral judgment model. Both time pressure and consideration of non-serious as opposed to serious moral dilemmas led to an increase in a justice orientation compared with a care orientation in moral judgments. In Experiment 2, a similar task was given to 80 persons of mixed age and profession, and the participants' moral reasoning was coded in terms of its being either duty-orientated (duty, obligations, rights) or consequence-oriented (effects on others). Men were found to be more duty-oriented than women, and time pressure to lead to a greater incidence of duty orientation.


Factors associated with the number and size of renal angiomyolipomas in sporadic angiomyolipoma (sAML): a study of adult patients with sAML managed in a Dutch tertiary referral center.
To describe the patient characteristics, treatments, disease monitoring, and kidney function of patients with sporadic angiomyolipoma (sAML), stratified by the number and size of renal angiomyolipomas (AMLs). Single-center retrospective analysis of patients with sAML treated from 1990 to 2015 in a dedicated clinic for inheritable tumor syndromes in a tertiary referral center from the Netherlands. Patients' first AML assessment at the clinic was defined as the index date. Patient characteristics were measured at the index date. Treatments, disease monitoring, and kidney function were measured post-index date. The study sample included 53 patients followed for a total of 184.6 patient-years. At the index date, the largest AML was ≥ 3.5 cm for 26 patients and < 3.5 cm for 27 patients (including six patients with five or more AMLs of < 3.5 cm). As compared to patients with AMLs < 3.5 cm, patients with largest AML ≥ 3.5 cm had higher frequency of pre-index bleeding episodes (31 vs. 4%), pre-index hypertension (35 vs. 15%), post-index nephrectomy (19 vs. 4%), post-index embolization (8 vs. 0%), and post-index renal scans (1.14 vs. 0.74 scans/year). Kidney impairment was especially pronounced in young adults with AML ≥ 3.5 cm. On average, patients with sAML developed chronic kidney disease stage two earlier than the general Dutch population (age 42 vs. 55 years), but later than the patients with tuberous sclerosis complex (35 years). Patients with sAML, especially those with larger AMLs, have high disease burden.


A new quality assessment parameter for optical coherence tomography.
To create a new, automated method of evaluating the quality of optical coherence tomography (OCT) images and to compare its image quality discriminating ability with the quality assessment parameters signal to noise ratio (SNR) and signal strength (SS). A new OCT image quality assessment parameter, quality index (QI), was created. OCT images (linear macular scan, peripapillary circular scan, and optic nerve head scan) were analysed using the latest StratusOCT system. SNR and SS were collected for each image. QI was calculated based on image histogram information using a software program of our own design. To evaluate the performance of these parameters, the results were compared with subjective three level grading (excellent, acceptable, and poor) performed by three OCT experts. 63 images of 21 subjects (seven each for normal, early/moderate, and advanced glaucoma) were enrolled in this study. Subjects were selected in a consecutive and retrospective fashion from our OCT imaging database. There were significant differences in SNR, SS, and QI between excellent and poor images (p = 0.04, p = 0.002, and p<0.001, respectively, Wilcoxon test) and between acceptable and poor images (p = 0.02, p<0.001, and p<0.001, respectively). Only QI showed significant difference between excellent and acceptable images (p = 0.001). Areas under the receiver operating characteristics (ROC) curve for discrimination of poor from excellent/acceptable images were 0.68 (SNR), 0.89 (IQP), and 0.99 (QI). A quality index such as QI may permit automated objective and quantitative assessment of OCT image quality that performs similarly to an expert human observer.


Surprising properties of a furo-furanone.
The electronic absorption, fluorescence, and excitation spectra of furo[3,4-c]furanone (1) have been measured in different solvents at different concentrations. We observed a complex dependence of absorption and excitation spectra as a function of the concentration in CH(2)Cl(2) and THF due to aggregate formation. Interestingly, the fluorescence spectra were not affected. Resolving the puzzle was made possible by the fact that 1 fits perfectly into the channels of zeolite L (ZL) microcrystals to form 1-ZL guest-host composites. The geometry of the ZL channel system ensures a well-defined orientation of the embedded dye molecules, thereby leading to a preferred orientation of their electronic transition dipole moment (ETDM) and thus to objects with pronounced optical anisotropy properties. This enabled us to understand that in solution the monomers that are present at low concentration form an aggregate in which the molecules sit on top of each other and arrange into a J-type aggregate configuration at higher concentrations. The signature of the latter is observed in the 1-ZL composites. This seems to be the first example in which the insertion of molecules into a nanochannel microcrystal has helped in understanding the weak intermolecular interactions that take place in solution.


Effects of visit-to-visit variability in systolic blood pressure on macrovascular and microvascular complications in patients with type 2 diabetes mellitus: the ADVANCE trial.
Recent evidence suggests that visit-to-visit variability in systolic blood pressure (SBP) and maximum SBP are predictors of cardiovascular disease. However, it remains uncertain whether these parameters predict the risks of macrovascular and microvascular complications in patients with type 2 diabetes mellitus. The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) was a factorial randomized controlled trial of blood pressure lowering and blood glucose control in patients with type 2 diabetes mellitus. The present analysis included 8811 patients without major macrovascular and microvascular events or death during the first 24 months after randomization. SBP variability (defined as standard deviation) and maximum SBP were determined during the first 24 months after randomization. During a median 2.4 years of follow-up from the 24-month visit, 407 major macrovascular (myocardial infarction, stroke, or cardiovascular death) and 476 microvascular (new or worsening nephropathy or retinopathy) events were observed. The association of major macrovascular and microvascular events with SBP variability was continuous even after adjustment for mean SBP and other confounding factors (both P<0.05 for trend). Hazard ratios (95% confidence intervals) for the highest tenth of SBP variability were 1.54 (0.99-2.39) for macrovascular events and 1.84 (1.19-2.84) for microvascular events in comparison with the lowest tenth. For maximum SBP, hazard ratios (95% confidence intervals) for the highest tenth were 3.64 (1.73-7.66) and 2.18 (1.04-4.58), respectively. Visit-to-visit variability in SBP and maximum SBP were independent risk factors for macrovascular and microvascular complications in type 2 diabetes mellitus. http://www.clinicaltrials.gov.


Altered localization of HrpZ in Pseudomonas syringae pv. syringae hrp mutants suggests that different components of the type III secretion pathway control protein translocation across the inner and outer membranes of gram-negative bacteria.
Pseudomonas syringae pv. syringae 61 (Pss61) secretes the HrpZ harpin by a type III protein secretion pathway encoded by a cluster of hrp (hypersensitive response and pathogenicity) and hrc genes. The nine hrc genes represent a subset of hrp genes that are also conserved in the type III virulence protein secretion systems of animal pathogenic Yersinia, Shigella, and Salmonella spp. The hrpJ and hrpU operons contain seven hrc genes (counting hrcQ(A) and hrcQ(B) as one gene), all with additional homologs involved in flagellar biogenesis and secretion, and five of which encode predicted inner membrane proteins. The hrpC and hrpZ operons encode HrcC and HrcJ, respectively, which are associated with the outer membrane. Interposon mutants affected in all of the hrc genes in the hrpJ and hrpU operons and TnphoA-induced hrcC and hrcJ mutants were assayed for altered localization of HrpZ in mid-log-phase cultures by immunoblotting sodium dodecyl sulfate-polyacrylamide gels that were run with various cell fractions. The hrpJ and hrpU operon mutants revealed a novel phenotype of partially reduced accumulation of HrpZ in the total culture (despite wild-type levels of hrpZ operon transcription), all of which was cell bound and equivalent in level to that of cell-bound HrpZ in the wild type. The hrcC and hrcJ mutant cultures accumulated the same total amount of HrpZ as the wild type, but the HrpZ was cell bound. Among all the strains tested, only the hrcC mutant accumulated significant amounts of HrpZ in the periplasm, as indicated by selective release through spheroplasting. Analysis of nonpolar mutations in the hrpU and hrpC operons support the results obtained with polar mutations. These observations indicate that a constant pool of HrpZ is maintained in the cytoplasm of Pss61 despite secretion deficiencies, that the hrpJ and hrpU operons encode an alternative to the Sec (general protein export) pathway for translocation across the inner membrane, that genes in the hrpC operon are necessary for translocation across the outer membrane, and that the Pss61 Hrp system permits study of two genetically distinguishable stages in type III protein secretion.


The relative validity and repeatability of an FFQ for estimating intake of zinc and its absorption modifiers in young and older Saudi adults.
To assess the relative validity and repeatability of a sixty-four-item FFQ for estimating dietary intake of Zn and its absorption modifiers in Saudi adults. In addition, we used the FFQ to investigate the effect of age and gender on these intakes. To assess validity, all participants completed the FFQ (FFQ1) and a 3 d food record. After 1 month, the FFQ was administered for a second time (FFQ2) to assess repeatability. Jeddah, Saudi Arabia. One hundred males and females aged 20-30 years and 60-70 years participated. Mean intakes of Zn and protein from FFQ1 were significantly higher than those from the food record while there were no detectable differences between tools for measurement of phytic acid intake. Estimated intakes of Zn, protein and phytate by both approaches were strongly correlated (P<0·001). Bland-Altman analysis showed for protein that the difference in intake as measured by the two methods was similar across the range of intakes while for Zn and phytic acid, the difference increased with increasing mean intake. Zn and protein intakes from FFQ1 and FFQ2 were highly correlated (r>0·68, P<0·001) but were significantly lower at the second measurement (FFQ2). Older adults consumed less Zn and protein compared with young adults. Intakes of all dietary components were lower in females than in males. The FFQ developed and tested in the current study demonstrated reasonable relative validity and high repeatability and was capable of detecting differences in intakes between age and gender groups.


Residues located on membrane-embedded flexible loops are essential for the second step of the apolipoprotein N-acyltransferase reaction.
Apolipoprotein N-acyltransferase (Lnt) is an essential membrane-bound enzyme that catalyzes the third and last step in the post-translational modification of bacterial lipoproteins. In order to identify essential residues implicated in substrate recognition and/or binding we screened for non-functional variants of Lnt obtained by error-prone polymerase chain reaction in a complementation assay using a lnt depletion strain. Mutations included amino acid substitutions in the active site and of residues located on flexible loops in the catalytic periplasmic domain. All, but one mutation, led to the formation of the thioester acyl-enzyme intermediate and to the accumulation of apo-Lpp, suggesting that these residues are involved in the second step of the reaction. A large cytoplasmic loop contains a highly conserved region and two hydrophobic segments. Accessibility analysis to alkylating reagents of substituted cysteine residues introduced in this region demonstrated that the hydrophobic segments do not completely span the membrane. Two residues in the highly conserved cytoplasmic region were shown to be essential for Lnt function. Together, our data suggest that amino acids located on flexible cytoplasmic and periplasmic loops, predicted to be membrane embedded, are required for efficient N-acylation of lipoproteins.


Serum soluble tumour necrosis factor receptor-2 (sTNFR2) as a biomarker of kidney tissue damage and long-term renal outcome in lupus nephritis.
We investigated the performance of soluble tumour necrosis factor receptor-2 (sTNFR2) as a biomarker of renal activity, damage, treatment response, and long-term outcome in lupus nephritis (LN). Serum sTNFR2 levels were assessed in 64 LN patients (52 proliferative, 12 membranous) before and after induction treatment, and in 314 non-lupus controls. In LN patients, renal biopsies were performed at baseline and post-treatment. Patients with ≥ 50% reduced proteinuria, normal or improved estimated glomerular filtration rate (eGFR) by ≥ 25%, and inactive urinary sediment were considered clinical responders (CRs). Patients with ≥ 50% improved renal activity index were considered histopathological responders (HRs). Long-term renal outcome was determined using the chronic kidney disease (CKD) stage after a median follow-up of 11.3 years. sTNFR2 levels were elevated in LN patients versus controls both at baseline (p < 0.001) and post-treatment (p < 0.001), and decreased following treatment (p < 0.001). Baseline sTNFR2 correlated with Chronicity Index scores in both baseline (r = 0.34, p = 0.006) and post-treatment (r = 0.43, p < 0.001) biopsies. In membranous LN, baseline sTNFR2 levels were higher in CRs (p = 0.048) and HRs (p = 0.03) than in non-responders, and decreased only in CRs (p = 0.03). Both baseline (p = 0.02) and post-treatment (p = 0.03) sTNFR2 levels were associated with decreasing eGFR throughout long-term follow-up, and post-treatment levels were higher in patients with long-term follow-up CKD stage ≥ 3 versus 1-2 (p = 0.008). Our data suggest serum sTNFR2 as a marker of kidney tissue damage and a predictor of long-term prognosis in LN, and merit further evaluation of sTNFR2 as a predictor of clinical and histopathological treatment outcomes in membranous LN.


Communication: An effective linear-scaling atomic-orbital reformulation of the random-phase approximation using a contracted double-Laplace transformation.
An atomic-orbital (AO) reformulation of the random-phase approximation (RPA) correlation energy is presented allowing to reduce the steep computational scaling to linear, so that large systems can be studied on simple desktop computers with fully numerically controlled accuracy. Our AO-RPA formulation introduces a contracted double-Laplace transform and employs the overlap-metric resolution-of-the-identity. First timings of our pilot code illustrate the reduced scaling with systems comprising up to 1262 atoms and 10 090 basis functions. .


Amiodarone-induced thyrotoxicosis. A review.
Amiodarone (AM), a potent class III anti-arrhythmic drug, is an iodine-rich compound with a structural resemblance to thyroid hormones triiodothyronine (T3) and thyroxine (T4). At the commonly employed doses, AM causes iodine overload up to 50-100 times the optimal daily intake, which may be responsible of a spectrum of effects on thyroid function often counterbalancing its heart benefits. Although most patients on chronic AM treatment remain euthyroid, a consistent proportion may develop thyrotoxicosis (AM-induced thyrotoxicosis, AIT) or hypothyroidism. AIT is more prevalent in iodine-deficient areas and is currently subdivided in two different clinico-pathological forms (AIT I and AIT II). AIT I develops in subjects with underlying thyroid disease, and is caused by an exacerbation by iodine load of thyroid autonomous function; AIT II occurs in patients with no underlying thyroid disease and is probably consequent to a drug-induced destructive thyroiditis. Mixed or indeterminate forms of AIT encompassing several features of both AIT I and AIT II may be also observed. The differential diagnosis between AIT I and AIT II (which is important for the choice of the appropriate therapy) is currently made on radioiodine uptake (RAIU), which may be high, normal or low but detectable in AIT I, while is consistently very low or undetectable in AIT II and on colour-flow Doppler sonography (CFDS) showing normal or increased vascularity in AIT I and absent vascularity in AIT II. Quite recently, studies carried out in our Units at the University of Cagliari (Italy) showed that sestaMIBI thyroid scintigraphy may represent the best single test to differentiate AIT I (showing increased MIBI retention) from AIT II (displaying no significant uptake). Treatment of AIT is dependent from its etiology. AIT usually responds to combined thionamides and potassium perchlorate (KClO4) therapy, AIT II generally responds to glucocorticoids, while indeterminate forms may require both therapeutic approaches. In patients with AIT I definitive treatment of hyperthyroidism by administration of (131)I, initially not feasible for the low RAIU and/or the risk of thyrotoxicosis exacerbation, is advised after normalization of iodine overload. To control severe AIT additional treatment with lithium carbonate, the use of short course of iopanoic acid and plasmapheresis have been also proposed. In cases resistant to medical treatment and/or in patients with severe cardiac diseases who cannot interrupt AM or require quick AM reintroduction, total thyroidectomy (possibly carried out by minimally invasive video-assisted technique) may be proposed after rapid correction of thyrotoxicosis with combination of thionamides, KClO4, corticosteroids and a short course of iopanoic acid.


Restoring depleted resources: Efficacy and mechanisms of change of an internet-based unguided recovery training for better sleep and psychological detachment from work.
This randomized controlled trial evaluated the efficacy of an Internet-based intervention, which aimed to improve recovery from work-related strain in teachers with sleeping problems and work-related rumination. In addition, mechanisms of change were also investigated. A sample of 128 teachers with elevated symptoms of insomnia (Insomnia Severity Index [ISI] ≥ 15) and work-related rumination (Cognitive Irritation Scale ≥ 15) was assigned to either an Internet-based recovery training (intervention condition [IC]) or to a waitlist control condition (CC). The IC consisted of 6 Internet-based sessions that aimed to promote healthy restorative behavior. Self-report data were assessed at baseline and again after 8 weeks. Additionally, a sleep diary was used starting 1 week before baseline and ending 1 week after postassessment. The primary outcome was insomnia severity. Secondary outcomes included perseverative cognitions (i.e., work-related rumination and worrying), a range of recovery measures and depression. An extended 6-month follow-up was assessed in the IC only. A serial multiple mediator analysis was carried out to investigate mechanisms of change. IC participants displayed a significantly greater reduction in insomnia severity (d = 1.37, 95% confidence interval: 0.99-1.77) than did participants of the CC. The IC was also superior with regard to changes in all investigated secondary outcomes. Effects were maintained until a naturalistic 6-month follow-up. Effects on insomnia severity were mediated by both a reduction in perseverative cognitions and sleep effort. Additionally, a greater increase in number of recovery activities per week was found to be associated with lower perseverative cognitions that in turn led to a greater reduction in insomnia severity. This study provides evidence for the efficacy of an unguided, Internet-based occupational recovery training and provided first evidence for a number of assumed mechanisms of change.


Influence of newborn health messages on care-seeking practices and community health behaviors among participants in the Zambia Chlorhexidine Application Trial.
Identifying and understanding traditional perceptions that influence newborn care practices and care-seeking behavior are crucial to developing sustainable interventions to improve neonatal health. The Zambia Chlorhexidine Application Trial (ZamCAT), a large-scale cluster randomized trial, assessed the impact of 4% chlorhexidine on neonatal mortality and omphalitis in Southern Province, Zambia. The main purpose of this post-ZamCAT qualitative study was to understand the impact of newborn care health messages on care-seeking behavior for neonates and the acceptability, knowledge, and attitudes towards chlorhexidine cord care among community members and health workers in Southern Province. Five focus group discussions and twenty-six in-depth interviews were conducted with mothers and health workers from ten health centers (5 rural and 5 peri-urban/urban). Community perceptions and local realities were identified as fundamental to care-seeking decisions and influenced individual participation in particular health-seeking behaviors. ZamCAT field monitors (data collectors) disseminated health messages at the time of recruitment at the health center and during subsequent home visits. Mothers noted that ZamCAT field monitors were effective in providing lessons and education on newborn care practices and participating mothers were able to share these messages with others in their communities. Although the study found no effect of chlorhexidine cord washes on neonatal mortality, community members had positive views towards chlorhexidine as they perceived that it reduced umbilical cord infections and was a beneficial alternative to traditional cord applications. The acceptability of health initiatives, such as chlorhexidine cord application, in community settings, is dependent on community education, understanding, and engagement. Community-based approaches, such as using community-based cadres of health workers to strengthen referrals, are an acceptable and potentially effective strategy to improve care-seeking behaviors and practices.


Heparin-induced thrombocytopenia in intensive care patients.
To summarize new information on frequency of heparin-induced thrombocytopenia (HIT) in patients treated in intensive care units (ICU), developments in the interpretation of assays for detecting anti-PF4/heparin antibodies, and treatment of HIT patients. All data on the frequency of laboratory-confirmed HIT in ICU patients were included; for laboratory testing of HIT and treatment of patients, this review focuses on recent data that became available in 2005 and 2006. HIT is a potentially life-threatening adverse effect of heparin treatment caused by platelet-activating antibodies of immunoglobulin G class usually recognizing complexes of platelet factor 4 and heparin. HIT is more often caused by unfractionated heparin than low-molecular-weight heparin and is more common in postsurgical than in medical patients. In the ICU setting, HIT is uncommon (0.3-0.5%), whereas thrombocytopenia from other causes is very common (30-50%). For laboratory diagnosis of HIT antibodies, both antigen assays and functional (platelet activation) assays are available. Both tests are very sensitive (high negative predictive value) but specificity is problematic, especially for the antigen assays, which also detect nonpathogenic immunoglobulin M and immunoglobulin A class antibodies. Detection of immunoglobulin M or immunoglobulin A antibodies could potentially lead to adverse events such as bleeding if a false diagnosis of HIT prompts replacement of heparin by an alternative anticoagulant. For treatment of HIT, three alternative anticoagulants are approved: the direct thrombin inhibitors, lepirudin and argatroban, and the heparinoid, danaparoid (not approved in the United States). Recent data indicate that the approved dosing regimens of the direct thrombin inhibitors are too high, especially in ICU patients. HIT affects <1% of ICU patients even though 30-50% develop thrombocytopenia. The choice of the optimal alternative anticoagulant depends on patient characteristics. Many ICU patients require lower doses of alternative anticoagulant than those recommended by the manufacturer.


Buchnera has changed flatmate but the repeated replacement of co-obligate symbionts is not associated with the ecological expansions of their aphid hosts.
Symbiotic associations with bacteria have facilitated important evolutionary transitions in insects and resulted in long-term obligate interactions. Recent evidence suggests that these associations are not always evolutionarily stable and that symbiont replacement, and/or supplementation of an obligate symbiosis by an additional bacterium, has occurred during the history of many insect groups. Yet, the factors favouring one symbiont over another in this evolutionary dynamic are not well understood; progress has been hindered by our incomplete understanding of the distribution of symbionts across phylogenetic and ecological contexts. While many aphids are engaged into an obligate symbiosis with a single Gammaproteobacterium, Buchnera aphidicola, in species of the Lachninae subfamily, this relationship has evolved into a 'ménage à trois', in which Buchnera is complemented by a cosymbiont, usually Serratia symbiotica. Using deep sequencing of 16S rRNA bacterial genes from 128 species of Cinara (the most diverse Lachninae genus), we reveal a highly dynamic dual symbiotic system in this aphid lineage. Most species host both Serratia and Buchnera but, in several clades, endosymbionts related to Sodalis, Erwinia or an unnamed member of the Enterobacteriaceae have replaced Serratia. Endosymbiont genome sequences from four aphid species confirm that these coresident symbionts fulfil essential metabolic functions not ensured by Buchnera. We further demonstrate through comparative phylogenetic analyses that cosymbiont replacement is not associated with the adaptation of aphids to new ecological conditions. We propose that symbiont succession was driven by factors intrinsic to the phenomenon of endosymbiosis, such as rapid genome deterioration or competitive interactions between bacteria with similar metabolic capabilities.


Attenuated activation of the anterior rostral medial prefrontal cortex on self-relevant social reward processing in individuals with autism spectrum disorder.
The social motivation hypothesis posits that people with autism spectrum disorder (ASD) find social stimuli less rewarding and are therefore less motivated towards social interaction than people with neuro-typical development (TD). However, the less rewarding social stimuli characteristics during social interaction for people with ASD are largely unknown. The contingent positive responsiveness of others relevant to self-action motivates the early development of social interaction, thus representing a social reward. As individuals with ASD often exhibit atypical responses to self-relevant stimuli in their early life, we hypothesized that the self-relevant responses of others are less rewarding for individuals with ASD. To test this hypothesis, we conducted a functional magnetic resonance imaging study using a social contingency task. During the task, the participants attempted to make the audience laugh by telling funny jokes and thus activating the anterior rostral medial prefrontal cortex (arMPFC) of TD individuals (Sumiya et al., 2017). We explicitly predicted that the atypical activation of the arMPFC is related to the reduced reward value of self-relevant responses to others in individuals with ASD. Thirty-one adults with ASD and 24 age- and intelligence quotient-matched TD adults participated in the study. Participants with ASD reported significantly lower pleasure after the audience's responses to their own actions than those in the TD group. Correspondingly, the self-related activation of the arMPFC, defined by the results of our previous study, was attenuated in the ASD group compared to the TD group. The present findings indicate that weak self-relevant outcome processing mediated by the arMPFC of individuals with ASD dampens the rewarding nature of social interaction.


Memory for fact, fiction, and misinformation: the Iraq War 2003.
Media coverage of the 2003 Iraq War frequently contained corrections and retractions of earlier information. For example, claims that Iraqi forces executed coalition prisoners of war after they surrendered were retracted the day after the claims were made. Similarly, tentative initial reports about the discovery of weapons of mass destruction were all later disconfirmed. We investigated the effects of these retractions and disconfirmations on people's memory for and beliefs about war-related events in two coalition countries (Australia and the United States) and one country that opposed the war (Germany). Participants were queried about (a) true events, (b) events initially presented as fact but subsequently retracted, and (c) fictional events. Participants in the United States did not show sensitivity to the correction of misinformation, whereas participants in Australia and Germany discounted corrected misinformation. Our results are consistent with previous findings in that the differences between samples reflect greater suspicion about the motives underlying the war among people in Australia and Germany than among people in the United States.


Smooth Sensor Motion Planning for Robotic Cyber Physical Social Sensing (CPSS).
Although many researchers have begun to study the area of Cyber Physical Social Sensing (CPSS), few are focused on robotic sensors. We successfully utilize robots in CPSS, and propose a sensor trajectory planning method in this paper. Trajectory planning is a fundamental problem in mobile robotics. However, traditional methods are not suited for robotic sensors, because of their low efficiency, instability, and non-smooth-generated paths. This paper adopts an optimizing function to generate several intermediate points and regress these discrete points to a quintic polynomial which can output a smooth trajectory for the robotic sensor. Simulations demonstrate that our approach is robust and efficient, and can be well applied in the CPSS field.


Whey Protein Concentrate Hydrolysate Prevents Bone Loss in Ovariectomized Rats.
Milk is known as a safe food and contains easily absorbable minerals and proteins, including whey protein, which has demonstrated antiosteoporotic effects on ovariectomized rats. This study evaluated the antiosteoporotic effect of whey protein concentrate hydrolysate (WPCH) digested with fungal protease and whey protein concentrate (WPC). Two experiments were conducted to determine (1) efficacy of WPCH and WPC and (2) dose-dependent impact of WPCH in ovariectomized rats (10 weeks old). In Experiment I, ovariectomized rats (n=45) were allotted into three dietary treatments of 10 g/kg diet of WPC, 10 g/kg diet of WPCH, and a control diet. In Experiment II, ovariectomized rats (n=60) were fed four different diets (0, 10, 20, and 40 g/kg of WPCH). In both experiments, sham-operated rats (n=15) were also fed a control diet containing the same amount of amino acids and minerals as dietary treatments. After 6 weeks, dietary WPCH prevented loss of bone, physical properties, mineral density, and mineral content, and improved breaking strength of femurs, with similar effect to WPC. The bone resorption enzyme activity (tartrate resistance acid phosphatase) in tibia epiphysis decreased in response to WPCH supplementation, while bone formation enzyme activity (alkaline phosphatase) was unaffected by ovariectomy and dietary treatment. Bone properties and strength increased as the dietary WPCH level increased (10 and 20 g/kg), but there was no difference between the 20 and 40 g/kg treatment. WPCH and WPC supplementation ameliorated bone loss induced by ovariectomy in rats.


Approach to distal femur by osteotomy of the patellar distal pole and internal fixation with basket plate in complex articular fracture: report of five cases.
According to AO classification, 33-C3 (complete articular multifragmentary) fracture of distal femur is characterized by complex articular involvement, along with short distal femoral block with multiple small fragments and usually with severe soft tissue abruption. In such cases of complex articular fracture of distal femur with extensive comminution of the femur condyle that is often seen in these fractures, anatomical reduction is quite difficult. Minimal fixation strategies sometimes do not provide an optimal degree of reduction and stability of the distal femoral block osteosynthesis. We describe 5 cases of treatment of the 33-C3 distal femoral fractures using arthrotomy of the knee joint by osteotomy of the distal pole of the patella and internal fixation with basket plate as an alternative approach for anatomical reduction of the comminuted articular surface.


Unraveling the Links Between the Initiation of Ventilation and Brain Injury in Preterm Infants.
The initiation of ventilation in the delivery room is one of the most important but least controlled interventions a preterm infant will face. Tidal volumes (V T) used in the neonatal intensive care unit are carefully measured and adjusted. However, the V Ts that an infant receives during resuscitation are usually unmonitored and highly variable. Inappropriate V Ts delivered to preterm infants during respiratory support substantially increase the risk of injury and inflammation to the lungs and brain. These may cause cerebral blood flow instability and initiate a cerebral inflammatory cascade. The two pathways increase the risk of brain injury and potential life-long adverse neurodevelopmental outcomes. The employment of new technologies, including respiratory function monitors, can improve and guide the optimal delivery of V Ts and reduce confounders, such as leak. Better respiratory support in the delivery room has the potential to improve both respiratory and neurological outcomes in this vulnerable population.


Exosomal tumor microRNA modulates premetastatic organ cells.
Tumor exosomes educate selected host tissues toward a prometastatic phenotype. We demonstrated this for exosomes of the metastatic rat adenocarcinoma BSp73ASML (ASML), which modulate draining lymph nodes and lung tissue to support settlement of poorly metastatic BSp73ASML-CD44v4-v7 knockdown (ASML-CD44v(kd)) cells. Now, we profiled mRNA and microRNA (miRNA) of ASML(wt) and ASML-CD44v(kd) exosomes to define the pathway(s), whereby exosomes prepare the premetastatic niche. ASML exosomes, recovered in draining lymph nodes after subcutaneous injection, preferentially are taken up by lymph node stroma cells (LnStr) and lung fibroblasts (LuFb) that were chosen as exosome targets. ASML(wt) and ASML-CD44v(kd) exosomes contain a restricted mRNA and miRNA repertoire that differs significantly between the two lines and exosomes thereof due to CD44v6 influencing gene and miRNA transcription/posttranscriptional regulation. Exosomal mRNA and miRNA are recovered in target cells, where transferred miRNA significantly affected mRNA translation. Besides others, this was exemplified for abundant ASML(wt)-exosomal miR-494 and miR-542-3p, which target cadherin-17 (cdh17). Concomitantly, matrix metalloproteinase transcription, accompanying cdh17 down-regulation, was upregulated in LnStr transfected with miR-494 or miR-542-3p or co-cultured with tumor exosomes. Thus, tumor exosomes target non-transformed cells in premetastatic organs and modulate premetastatic organ cells predominantly through transferred miRNA, where miRNA from a metastasizing tumor prepares premetastatic organ stroma cells for tumor cell hosting. Fitting the demands of metastasizing tumor cells, transferred exosomal miRNA mostly affected proteases, adhesion molecules, chemokine ligands, cell cycle- and angiogenesis-promoting genes, and genes engaged in oxidative stress response. The demonstration of function-competent exosomal miRNA in host target cells encourages exploiting exosomes as a therapeutic gene delivery system.


Enhanced expression of Aggrus (T1alpha/podoplanin), a platelet-aggregation-inducing factor in lung squamous cell carcinoma.
Aggrus (T1alpha/podoplanin, known as a specific marker for type I alveolar cells or lymphatic endothelial cells) is a transmembrane sialoglycoprotein that aggregates platelets. Previously, we showed that upregulated expression of Aggrus occurs in colorectal tumors or testicular tumors and could be associated with platelet-aggregating activity and metastatic ability. In testicular tumors, Aggrus is specifically expressed in seminoma. The present study investigates Aggrus expression in human primary lung cancer tissues of different types. Microarray analysis demonstrated that aggrus was significantly expressed in squamous cell carcinoma (10/15; 66.7%). Immunohistochemical analysis also showed that the incidence of positive staining in sections of squamous cell carcinoma (7/8; 87.5%) was higher than that in adenocarcinoma (2/13; 15.4%). Furthermore, Aggrus expression was detected in a squamous cell carcinoma cell line, NCI-H226, by real-time PCR. These findings indicated that overexpression of Aggrus occurred in squamous cell carcinoma of the lung. Therefore, Aggrus could be a useful diagnostic marker for squamous cell carcinoma of the lung.


Fluorescence diffuse optical tomography with functional and anatomical a priori information: feasibility study.
Fluorescence diffuse optical tomography (FT) is an emerging molecular imaging technique that can spatially resolve both fluorophore concentration and lifetime parameters. In this study, we investigate the performance of a frequency-domain FT system for small inclusions that are embedded in a heterogeneous background. The results demonstrate that functional and structural a priori information is crucial to be able to recover both parameters with high accuracy. The functional a priori information is defined by the absorption and scattering maps at both excitation and emission wavelengths. Similarly, the boundaries of the small inclusion and different regions in the background are utilized as the structural a priori information. Without a priori information, the fluorophore concentration of a 5 mm inclusion in a 40 mm medium is recovered with 50% error, while the lifetime cannot be recovered at all. On the other hand, when both functional and structural information are available, the true lifetime can be recovered and the fluorophore concentration can be estimated only with 5% error. This study shows that a hybrid system that can acquire diffuse optical absorption tomography (DOT), FT and anatomical images in the same setting is essential to be able to recover the fluorophore concentration and lifetime accurately in vivo.


The Evidence-based Practice Attitude Scale-36 (EBPAS-36): a brief and pragmatic measure of attitudes to evidence-based practice validated in US and Norwegian samples.
Short and valid instruments for measuring factors facilitating or hindering implementation efforts are called for. This article describes (1) the adaptation of a shorter version of the Evidence-based Practice Attitude Scale (EBPAS-50 items), and (2) the psychometric properties of the shortened version in both US and Norwegian data. The US participants were mental health service providers (N = 418) recruited from clinics providing mental health services in San Diego County, California. The Norwegian participants were psychologists, psychiatric nurses, and psychology students (N = 838) recruited from the Norwegian Psychological Association and the Norwegian Nurses Organization. A confirmatory factor analysis (CFA) approach was used. The reduction resulted in 36 items named EBPAS-36, and the original 12 factor model was maintained. The EBPAS-36 had acceptable model fit, as indicated by a low degree of misspecification errors in both the US (RMSEA = .045 (CI90% .040-.049); SRMR = .05) and the Norwegian data (RMSEA = .052 (CI90% .047-.056, SRMR = .07). Incremental model fit was fair in the US (CFI = .93, TLI = .91) and in the Norwegian samples (CFI = .91, TLI = .89). The internal consistency (Cronbach's α) in the US and the Norwegian samples were good for the total EBPAS-36 score (.79 and .86, respectively) and were ranged from adequate to excellent for the subscales (US .60-.91 and Norway .61-.92). The EBPAS-36 has adequate psychometric properties both in US and Norwegian samples, hence indicating cross-cultural validity. It is a brief, pragmatic, and more user-friendly instrument than the EBPAS-50, yet maintains a broad scope by retaining the original 12 measurement domains.


Photoinduced Bimolecular Electron Transfer in Ionic Liquids.
The present work seeks to better understand the role of solute diffusion and solvation dynamics on bimolecular electron transfer in ionic liquids (ILs). Steady-state and time-resolved measurements of the reductive fluorescence quenching of five fluorophores ("F") by six quenchers ("Q"; electron donors) are reported in acetonitrile and two ionic liquids, 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)amide and trihexyl(tetradecyl)phosphonium bis(trifluoromethylsulfonyl)amide. Data were collected on 66 different F-Q-solvent systems, which span a 2.0 eV range in driving force and viscosities that vary 1000-fold, enabling stringent tests of bimolecular electron transfer models. A Stern-Volmer analysis yielded much larger diffusion-limited rates than simple kinetic theory predictions in the ILs and the absence of a Marcus turnover. Use of an approximate solution to the spherical diffusion-reaction equation enabled testing of several models for the reaction rate distance dependence. The Smoluchowski and Collins-Kimball models, which assume reaction at a single distance, are able to fit the data collected in acetonitrile solutions reasonably well, but not the data in the IL solvents. An extended sink model, incorporating a finite reaction zone, was able to fit all data satisfactorily with only three adjustable parameters. Diffusion coefficients extracted from these fits were much larger for the neutral versus anionic quenchers and close to predicted values. Molecular dynamics simulations and density-functional methods were then used to explore solvation structures and electronic couplings. The electronic coupling between contact F-Q pairs was found to vary strongly with the relative location and orientation of the reactants. Information from these simulations was used to constrain a model based on classical Marcus theory, which provided physically reasonable fits with only two adjustable parameters, but required systematic reduction of the driving forces in order to suppress a rate turnover at large driving force. The latter requirement indicates that reaction rates in ionic liquids are limited by some factor not properly accounted for in bimolecular electron transfer models based on a spherical diffusion-reaction approach. Small-amplitude motions within contact F-Q pairs, which gate the electronic coupling, are suggested to be the limiting dynamics.