Effect of HU protein on the conformation and compaction of DNA in a nanochannel.
The effect of the heat unstable nucleoid structuring protein HU on the conformation of single DNA molecules confined in a nanochannel was investigated with fluorescence microscopy. Pre-incubated DNA molecules contract in the longitudinal direction of the channel with increasing concentration of HU. This contraction is mainly due to HU-mediated bridging of distal DNA segments and is controlled by channel diameter as well as ionic composition and strength of the buffer. For over-threshold concentrations of HU, the DNA molecules compact into an condensed form. Divalent magnesium ions facilitate, but are not required for bridging nor condensation. The conformational response following exposure to HU was investigated with a nanofluidic device that allows an in situ change in environmental solution conditions. The stretch of the nucleoprotein complex first increases, reaches an apex in ∼20 min, and subsequently decreases to an equilibrium value pertaining to pre-incubated DNA molecules after ∼2 h. This observation is rationalised in terms of a time-dependent bending rigidity by structural rearrangement of bound HU protein followed by compaction through bridging interaction. Results are discussed in regard to previous results obtained for nucleoid associated proteins H-NS and Hfq, with important implications for protein binding related gene regulation.


Research ethics: ethical issues of data reporting and the quest for authenticity.
The search for truth and its unbiased reporting are ultimate goals of conducting scientific research. Ideally, the reporting of research data ought to be an objective task. In practice, however, it is fraught with numerous statistical and ethical pitfalls, seldom addressed in formal emergency medicine training. The lure of academic celebrity and related influences may persuade researchers to report results in ways that make data appear more interesting, or worthy of publication. Several examples of potentially misleading data reporting are illustrated, including using inappropriate statistical tests, neglecting negative results, omitting missing data points, failing to report actual numbers of eligible subjects, using inappropriate graph labels or terminology, data dredging, and others. Although potentially inaccurate or inflated methods of data reporting may not constitute overt scientific misconduct, the intentional misrepresentation of data is a form of fraud or deception. Publicly funded academic inquiry is a privilege and honor enjoyed by a trusted few. Regardless of outcome, every effort should be made to report data in the most scientifically accurate method. To this end, the Society for Academic Emergency Medicine Code of Conduct and American College of Emergency Physicians Code of Ethics provide important guidance toward the accurate, compassionate, competent, impartial, and honest conduct of scientific research. Accuracy and authenticity in data reporting are first and foremost a matter of individual integrity, and are crucial to the preservation of academic credibility, the protection of future patients, and the public's trust in the medical research enterprise.


Theoretical foundations of spatially-variant mathematical morphology part I: binary images.
We develop a general theory of spatially-variant (SV) mathematical morphology for binary images in the Euclidean space. The basic SV morphological operators (i.e., SV erosion, SV dilation, SV opening and SV closing) are defined. We demonstrate the ubiquity of SV morphological operators by providing a SV kernel representation of increasing operators. The latter representation is a generalization of Matheron's representation theorem of increasing and translation-invariant operators. The SV kernel representation is redundant, in the sense that a smaller subset of the SV kernel is sufficient for the representation of increasing operators. We provide sufficient conditions for the existence of the minimal basis representation in terms of upper-semi-continuity in the hit-or-miss topology. The latter minimal basis representation is a generalization of Maragos' minimal basis representation for increasing and translation-invariant operators. Moreover, we investigate the upper-semi-continuity property of the basic SV morphological operators. Several examples are used to demonstrate that the theory of spatially-variant mathematical morphology provides a general framework for the unification of various morphological schemes based on spatiallyvariant geometrical structuring elements (e.g., circular, affine and motion morphology). Simulation results illustrate the theory of the proposed spatially-variant morphological framework and show its potential power in various image processing applications.


Individual, physical and psychological risk factors for neck pain in Australian office workers: a 1-year longitudinal study.
Neck pain is more prevalent in office workers than in the general community. To date, findings from prospective studies that investigated causal relationships between putative risk factors and the onset of neck pain in this population have been limited by high loss to follow-up. The aim of this research was to prospectively evaluate a range of risk factors for neck pain in office workers, using validated and reliable objective measures as well as attain an estimate of 1-year incidence. We assembled a cohort of 53 office workers without neck pain and measured individual, physical, workplace and psychological factors at baseline. We followed participants for 1 year to measure the incidence of neck pain. We achieved 100% participant follow-up. Cox regression analysis was applied to examine the relationship between the putative risk factors and the cumulative incidence of neck pain. The 1-year incidence proportion of neck pain in Australian office workers was estimated in this study to be 0.49 (95% CI 0.36-0.62). Predictors of neck pain with moderate to large effect sizes were female gender (HR: 3.07; 95% CI: 1.18-7.99) and high psychological stress (HR: 1.64; 95% CI: 0.66-4.07). Protective factors included increased mobility of the cervical spine (HR: 0.44; 95% CI: 0.19-1.05) and frequent exercise (HR: 0.64; 95% CI: 0.27-1.51). These results reveal that neck pain is common in Australian office workers and that there are risk factors that are potentially modifiable.


Neprilysin, the kidney brush border neutral proteinase: a possible potential target for ischemic renal injury.
Neprilysin (NEP) is an endogenously induced peptidase for modulating production and degradation of various peptides in humans. It is most abundantly present in kidney and regulates the intrinsic renal homeostatic mechanism. Recently, drugs inhibiting NEP have been approved for the use in heart failure. In the context of increased prevalence of ischemia associated renal failure, NEP could be an attractive target for treating kidney failure. In the kidney, targeting NEP may possess potential benefits as well as adverse consequences. The unfavorable outcomes of NEP are mainly attributed to the degradation of the natriuretic peptides (NPs). NPs are involved in the inhibition of the renin-angiotensin-aldosterone system (RAAS) and activation of the sympathetic system contributing to the tubular and glomerular injury. In contrary, NEP exerts the beneficial effect by converting angiotensin-1 (Ang I) to angiotensin-(1-7) (Ang-(1-7)), thus activating MAS-related G-protein coupled receptor. MAS receptor antagonizes angiotensin type I receptor (AT-1R), reduces reactive oxygen species (ROS) and inflammation, thus ameliorating renal injury. However, the association of NEP with complex cascades of renal ischemia remains vague. Therefore, there is a need to evaluate the putative mechanism of NEP and its overlap with other signaling cascades in conditions of renal ischemia.


Inhibition of rat brain glutamate receptors by philanthotoxin.
The actions of philanthotoxin (PhTX) were studied on the function of glutamate receptors expressed in Xenopus oocytes injected with rat brain mRNA and on binding of radioligands to rat brain glutamate receptors. PhTX reversibly inhibited the oocyte responses to quisqualate, N-methyl-D-aspartate (NMDA) and kainate in a dose-dependent manner. The NMDA receptor was the most sensitive to PhTX action (10-fold more than the kainate receptor) and the least sensitive was the smooth current component of the quisqualate response. Recovery from PhTX block differed among the three amino acids. NMDA responses recovered completely within a few minutes whereas responses to kainate and quisqualate recovered more slowly. PhTX had no effect on equilibrium binding of [3H]glutamate to rat brain cortical membranes studied in buffer treated to eliminate microorganisms. Based on the drug specificity of this [3H]glutamate binding, it is suggested to be mostly to the NMDA receptor. Low concentrations of PhTX (1-10 microM) potentiated binding of [3H] MK-801, a specific noncompetitive inhibitor of the NMDA receptor. However, higher PhTX concentrations inhibited this binding with an IC50 of 20 microM, similar to its inhibition of the oocyte-expressed NMDA receptor. Inhibition of [3H]MK-801 binding by PhTX was noncompetitive. It is suggested that PhTX, like the more potent MK-801, binds to an allosteric site on the NMDA receptor and inhibits its function but its binding site is not identical with the MK-801 binding site.


Dyslexia and familial high blood pressure: an observational pilot study.
Developmental dyslexia is a neurodevelopmental learning disability characterised by unexpectedly poor reading and unknown aetiology. One hypothesis proposes excessive platelet activating factor, a potent vasodilator, as a contributor, implying that there should be a negative association between dyslexia and high blood pressure (HBP). Since both conditions have a partial genetic basis, this association may be apparent at the familial level. To test this prediction in dyslexic and non-dyslexic children. Individuals and families with (HBP+) and without (HBP-) a family history of HBP were compared. Proportionately fewer dyslexics (49/112) than controls (11/12) were HBP+. Families with multiple, all dyslexic children were less likely to be HBP+ (7/16) than those with a non-dyslexic child (11/11). Within families, mean child scores on reading were higher in the HBP+ group (mean 44.3, SE 0.95) than in the HBP- group (mean 40.3, SE 0.87). HBP+ family history is associated with better performance on reading. The prediction of a negative association between dyslexic status and familial high blood pressure is therefore confirmed.


Generation of vector beams in planar photonic crystal cavities with multiple missing-hole defects.
We propose a novel method to generate vector beams in planar photonic crystal cavities with multiple missing-hole defects. Simulating the resonant modes in the cavities, we observe that the optical fields in each defect have different phase and polarization state distributions, which promise the compositions of vector beams by the scattered light from the defects. The far-field radiation patterns of the cavity modes calculated via the Sommerfeld diffraction theory present vector beams possessing hollow intensity profiles and polarization singularities. In addition, the extraction efficiencies of the vector beams from the cavities could be improved by modifying the air-holes surrounding the defects. This planar photonic crystal cavity-based vector beam generator may provide useful insights for the on-chip controlling of vector beams in their propagations and interactions with matter.


Neutrophil gelatinase-associated lipocalin is a predictor of the course of global and renal childhood-onset systemic lupus erythematosus disease activity.
To determine whether neutrophil gelatinase-associated lipocalin (NGAL) can predict worsening of global and renal disease activity in childhood-onset systemic lupus erythematosus (SLE). One hundred eleven patients with childhood-onset SLE were enrolled in a longitudinal, prospective study with quarterly study visits and had at least 3 study visits. At each visit, global disease activity was measured using 3 external standards: the numerically converted British Isles Lupus Assessment Group (BILAG) index, the SLE Disease Activity Index 2000 update score, and the physician's assessment of global disease activity. Renal and extrarenal disease activity were measured by the respective domain scores. The disease course over time was categorized at the most recent visit (persistently active, persistently inactive, improved, or worsening). Plasma and urinary NGAL levels were measured by enzyme-linked immunosorbent assay, and urinary NGAL levels were standardized to the urinary creatinine concentration. The longitudinal changes in NGAL levels were compared with the changes in SLE disease activity using mixed-effect models. Significant increases in standardized urinary NGAL levels of up to 104% were detected up to 3 months before worsening of lupus nephritis (as measured by all 3 external standards). Plasma NGAL levels increased significantly by as much as 26% up to 3 months before worsening of global SLE disease activity as measured by all 3 external standards. Plasma NGAL levels increased significantly by 26% as early as 3 months prior to worsening of lupus nephritis as measured by the BILAG renal score. Serial measurement of urinary and plasma NGAL levels may be valuable in predicting impending worsening of global and renal childhood-onset SLE disease activity.


Endocannabinoids and the gastrointestinal tract.
In the past centuries, different preparations of marijuana have been used for the treatment of gastrointestinal (GI) disorders, such as GI pain, gastroenteritis and diarrhea. Delta9-tetrahydrocannabinol (THC; the active component of marijuana), as well as endogenous and synthetic cannabinoids, exert their biological functions on the gastrointestinal tract by activating two types of cannabinoid receptors, cannabinoid type 1 receptor (CB1 receptor) and cannabinoid type 2 receptor (CB2 receptor). While CB1 receptors are located in the enteric nervous system and in sensory terminals of vagal and spinal neurons and regulate neurotransmitter release, CB2 receptors are mostly distributed in the immune system, with a role presently still difficult to establish. Under pathophysiological conditions, the endocannabinoid system conveys protection to the GI tract, eg from inflammation and abnormally high gastric and enteric secretion. For such protective activities, the endocannabinoid system may represent a new promising therapeutic target against different GI disorders, including frankly inflammatory bowel diseases (eg, Crohn's disease), functional bowel diseases (eg, irritable bowel syndrome), and secretion- and motility-related disorders.


Time trends and age-period-cohort analysis of cutaneous malignant melanoma incidence rates in the Romagna Region (northern Italy), 1986-2014.
After a long-term increase, the incidence of cutaneous malignant melanoma has stabilized recently or even decreased in several populations of North-western Europe, USA, Canada, Australia and New Zealand, but not in southern Europe. The incidence trends of primary invasive cutaneous malignant melanoma (International Classification of Diseases, 10th revision, codes C43.0-C43.9) in the Romagna Region (northern Italy, 1.2 million inhabitants) for the period 1986-2014 were analysed with an age-period-cohort modelling approach. The series included 2466 men and 2481 women, a total of 4947 patients. Using the method of model building, the best-fitting models were found to be an age-drift model for men and an age-period model for women. Among men, the age-specific incidence rates increased in each successive cohort born between 1916 and 1981 with an attenuation of the trend for younger ones in the last cohorts. Among younger women, a slight decrease occurred for the cohorts born after 1961. For men, the quasi-parallel appearance of incidence curves by age group and cohort on a log scale suggested that the observed change was explained by a linear cohort effect. For women, the curves tended to overlap, suggesting an interaction between age and cohort that could be explained as a nonlinear period effect. In conclusion, the long-term upward incidence trend in the study area is stabilizing among women and an attenuation of the increasing trend is occurring among younger men in the most recent cohorts. These observations need to be confirmed with longer-term studies.


The Healthy Nasal Cavity-Characteristics of Morphology and Related Airflow Based on a Statistical Shape Model Viewed from a Surgeon's Perspective.
Functional surgery on the nasal framework requires referential criteria to objectively assess nasal breathing for indication and follow-up. This motivated us to generate a mean geometry of the nasal cavity based on a statistical shape model. In this study, the authors could demonstrate that the introduced nasal cavity's mean geometry features characteristics of the inner shape and airflow, which are commonly observed in symptom-free subjects. Therefore, the mean geometry might serve as a reference-like model when one considers qualitative aspects. However, to facilitate quantitative considerations and statistical inference, further research is necessary. Additionally, the authors were able to obtain details about the importance of the isthmus nasi and the inferior turbinate for the intranasal airstream.


Anion-exchange reactions: facile and general access to sensitive photoelectrochemical platforms for biomarker immunosensing.
Affordable methodologies for detecting tumor markers at low concentrations are very important for early diagnosis. The two key requirements for designing ultrasensitive photoelectrochemical (PEC) immunosensors are highly active PEC platforms and amplified recognition events on the transducer surfaces. Herein we report the development of an effective and general strategy for the sensitive immunoassay of biomarkers using a novel PEC platform. In particular, in contrast to traditional photoanode materials prepared by introducing well-stabilized quantum dots onto an electrode, in this work CdSe nanocrystal (NC)-based PEC films were first formed directly on an ITO surface by an anion-exchange reaction and followed by coverage with organic stabilizers. The compacted CdSe film produces ultrahigh photocurrent signals under visible-light irradiation (λ = 470 nm). Using rabbit immunoglobulin G (RIgG) as a model biomarker, we showed that through biotin-avidin bridges, biotin-functionalized peroxidase (B-HRP) could be further assembled and could catalyze the conversion of its substrate, 4-chloro-1-naphthol (4-CN), to realize precipitation of nonconductive benzo-4-chlorohexadienone on the CdSe surface, thus resulting in blocking of the electron donors and absorption of the incident light. As the resulting photocurrent decrease was directly related to the target concentration, a sensitive PEC immunoassay could be constructed. The target RIgG was detected over a concentration range from 1.0 fg mL-1 to 10 μg mL-1 with an ultralow detection limit of 0.5 fg mL-1. This study presents a promising and general strategy for the development of highly sensitive PEC biosensors, which can be extended to the detection of other enzymes and biomolecules.


Relationships among Socioeconomic Factors and Self-rated Health in Japanese Adults: NIPPON DATA2010.
The distributions of socioeconomic status (SES) factors have been changing in Japan. We examined the relationships among SES and self-rated health (SRH) in Japanese adults. We analyzed 1,178 men and 1,555 women. We showed the distribution of SRH by sex and age and examined cross-sectional relationships among educational attainment, marital/living statuses, working status, household income and expenditure, and fine SRH (defined as excellent, very good, or good). We adjusted for age, subjective symptoms, visiting doctors, monthly equivalent household expenditure (EHE), and living in their own house. The age-standardized prevalence of fine SRH was 79% and 73% among men and women, respectively. Among men, graduating from high school (adjusted odds ratio [aOR] 1.53; 95% confidence interval [CI], 1.07-2.19, relative to graduating from elementary or junior high school) and university or junior college (aOR 1.74; 95% CI, 1.15-2.62) was associated with fine SRH. Among women, graduating from university or junior college was associated with fine SRH (aOR 1.65; 95% CI, 1.12-2.46). Neither marital/living status nor working status was associated with SRH after adjustments for age in either sex. Among women, high EHE and income were associated with fine SRH (the highest expenditure group: aOR 1.80; 95% CI, 1.22-2.65; the highest income group: aOR 2.15; 95% CI, 1.34-3.46, relative to the corresponding lowest group). These simple relationships were not observed for men. High educational attainment was associated with fine SRH. Relationships among household income, EHE, and fine SRH differed by sex.


Synthesizing and databasing fossil calibrations: divergence dating and beyond.
Divergence dating studies, which combine temporal data from the fossil record with branch length data from molecular phylogenetic trees, represent a rapidly expanding approach to understanding the history of life. National Evolutionary Synthesis Center hosted the first Fossil Calibrations Working Group (3-6 March, 2011, Durham, NC, USA), bringing together palaeontologists, molecular evolutionists and bioinformatics experts to present perspectives from disciplines that generate, model and use fossil calibration data. Presentations and discussions focused on channels for interdisciplinary collaboration, best practices for justifying, reporting and using fossil calibrations and roadblocks to synthesis of palaeontological and molecular data. Bioinformatics solutions were proposed, with the primary objective being a new database for vetted fossil calibrations with linkages to existing resources, targeted for a 2012 launch.


Overexpression of SOX2 Is Associated with Better Overall Survival in Squamous Cell Lung Cancer Patients Treated with Adjuvant Radiotherapy.
The purpose of this study is to investigate the prognostic significance of SOX2 gene amplification and expression in patients with American Joint Committee on Cancer stage III lung squamous cell carcinoma (SCC) who underwent surgery followed by adjuvant radiotherapy. Pathological specimens were obtained from 33 patients with stage III lung SCC treated with surgery followed by adjuvant radiotherapy between 1996 and 2008. SOX2 gene amplification and protein expression were analyzed using fluorescent in situ hybridization and immunohistochemistry, respectively. Patients were divided into two groups according to their SOX2 gene amplification and protein expression status. Kaplan-Meier estimates and a Cox proportional hazards model were used to identify the prognostic factors affecting patient survival. The median follow-up period for surviving patients was 58 months (range, 5 to 102 months). SOX2 gene amplification was observed in 22 patients and protein overexpression in 26 patients. SOX2 overexpression showed significant association with SOX2 gene amplification (p=0.002). In multivariate analysis, SOX2 overexpression was a significant prognostic factor for overall survival (OS) (hazard ratios [HR], 0.1; 95% confidence interval [CI], 0.002 to 0.5; p=0.005) and disease-free survival (DFS) (HR, 0.15; 95% CI, 0.04 to 0.65; p=0.01). Age (HR, 0.33; 95% CI, 0.11 to 0.98; p=0.046) and total radiation dose (HR, 0.13; 95% CI, 0.02 to 0.7; p=0.02) were the independent prognostic factors for OS and DFS. Patients with SOX2 amplification did not show a longer OS (p=0.95) and DFS (p=0.48). Our data suggested that SOX2 overexpression could be used as a positive prognostic factor in patients with stage III lung SCC receiving adjuvant radiotherapy.


Vitis vinifera berry metabolic composition during maturation: Implications of defoliation.
Leaves are an important contributor toward berry sugar and nitrogen (N) accumulation, and leaf area, therefore, affects fruit composition during grapevine (Vitis vinifera) berry ripening. The aim of this study was to investigate the impact of leaf presence on key berry quality attributes in conjunction with the accumulation of primary berry metabolites. Shortly after the start of véraison (berry ripening), potted grapevines were defoliated (total defoliation and 25% of the control), and the accumulation of berry soluble solids, N and anthocyanins were compared to that of a full leaf area control. An untargeted approach was undertaken to measure the content in primary metabolites by gas chromatography/mass spectrometry. Partial and full defoliation resulted in reduced berry sugar and anthocyanin accumulation, while total berry N content was unaffected. The juice yeast assimilable N (YAN), however, increased upon partial and full defoliation. Remobilized carbohydrate reserves allowed accumulation of the major berry sugars during the absence of leaf photoassimilation. Berry anthocyanin biosynthesis was strongly inhibited by defoliation, which could relate to the carbon (C) source limitation and/or increased bunch exposure. Arginine accumulation, likely resulting from reserve translocation, contributed to increased YAN upon defoliation. Furthermore, assessing the implications on various products of the shikimate pathway suggests the C flux through this pathway to be largely affected by leaf source limitation during fruit maturation. This study provides a novel investigation of impacts of leaf C and N source presence during berry maturation, on the development of key berry quality parameters as underlined by alterations in primary metabolism.


Effect of diet on excretion of estrogens in pre- and postmenopausal women.
Fecal, urinary, and plasma estrogens and plasma androgens were studied in healthy pre- and postmenopausal vegetarian and omnivorous women. Dietary histories of the subjects revealed that omnivores consumed a higher percentage of total protein and fat from animal sources. The total 72-hr fecal excretion as measured by dry weight was higher for vegetarians. Preliminary results indicate that vegetarian women excrete 2 to 3 times more estrogens in feces than do omnivores and that omnivores have about 50% higher mean plasma level of unconjugated estrone and estradiol than vegetarians. Estriol-3-glucuronide, a compound that is formed upon reabsorption of free estriol from the intestine, is found in lower concentrations in the urine of vegetarians. These data suggest that in vegetarians a greater amount of the biliary estrogens escape reabsorption and are excreted with the feces. The differences in estrogen metabolism may explain the lower incidence of breast cancer in vegetarian women.


Automatic range image registration in the Markov chain.
In this paper, a novel entropy that can describe both long and short-tailed probability distributions of constituents of a thermodynamic system out of its thermodynamic limit is first derived from the Lyapunov function for a Markov chain. We then maximize this entropy for the estimation of the probabilities of possible correspondences established using the traditional closest point criterion between two overlapping range images. When we change our viewpoint to look carefully at the minimum solution to the probability estimate of the correspondences, the iterative range image registration process can also be modeled as a Markov chain in which lessons from past experience in estimating those probabilities are learned. To impose the two-way constraint, outliers are explicitly modeled due to the almost ubiquitous occurrence of occlusion, appearance, and disappearance of points in either image. The estimated probabilities of the correspondences are finally embedded into the powerful mean field annealing scheme for global optimization, leading the camera motion parameters to be estimated in the weighted least-squares sense. A comparative study using real images shows that the proposed algorithm usually outperforms the state-of-the-art ICP variants and the latest genetic algorithm for automatic overlapping range image registration.


Comparison of fatty liver index with noninvasive methods for steatosis detection and quantification.
To compare noninvasive methods presently used for steatosis detection and quantification in nonalcoholic fatty liver disease (NAFLD). Cross-sectional study of subjects from the general population, a subgroup from the First Israeli National Health Survey, without excessive alcohol consumption or viral hepatitis. All subjects underwent anthropometric measurements and fasting blood tests. Evaluation of liver fat was performed using four noninvasive methods: the SteatoTest; the fatty liver index (FLI); regular abdominal ultrasound (AUS); and the hepatorenal ultrasound index (HRI). Two of the noninvasive methods have been validated vs liver biopsy and were considered as the reference methods: the HRI, the ratio between the median brightness level of the liver and right kidney cortex; and the SteatoTest, a biochemical surrogate marker of liver steatosis. The FLI is calculated by an algorithm based on triglycerides, body mass index, γ-glutamyl-transpeptidase and waist circumference, that has been validated only vs AUS. FLI < 30 rules out and FLI ≥ 60 rules in fatty liver. Three hundred and thirty-eight volunteers met the inclusion and exclusion criteria and had valid tests. The prevalence rate of NAFLD was 31.1% according to AUS. The FLI was very strongly correlated with SteatoTest (r = 0.91, P < 0.001) and to a lesser but significant degree with HRI (r = 0.55, P < 0.001). HRI and SteatoTest were significantly correlated (r = 0.52, P < 0.001). The κ between diagnosis of fatty liver by SteatoTest (≥ S2) and by FLI (≥ 60) was 0.74, which represented good agreement. The sensitivity of FLI vs SteatoTest was 85.5%, specificity 92.6%, positive predictive value (PPV) 74.7%, and negative predictive value (NPV) 96.1%. Most subjects (84.2%) with FLI < 60 had S0 and none had S3-S4. The κ between diagnosis of fatty liver by HRI (≥ 1.5) and by FLI (≥ 60) was 0.43, which represented only moderate agreement. The sensitivity of FLI vs HRI was 56.3%, specificity 86.5%, PPV 57.0%, and NPV 86.1%. The diagnostic accuracy of FLI for steatosis > 5%, as predicted by SteatoTest, yielded an area under the receiver operating characteristic curve (AUROC) of 0.97 (95% CI: 0.95-0.98). The diagnostic accuracy of FLI for steatosis > 5%, as predicted by HRI, yielded an AUROC of 0.82 (95% CI: 0.77-0.87). The κ between diagnosis of fatty liver by AUS and by FLI (≥ 60) was 0.48 for the entire sample. However, after exclusion of all subjects with an intermediate FLI score of 30-60, the κ between diagnosis of fatty liver by AUS and by FLI either ≥ 60 or < 30 was 0.65, representing good agreement. Excluding all the subjects with an intermediate FLI score, the sensitivity of FLI was 80.3% and the specificity 87.3%. Only 8.5% of those with FLI < 30 had fatty liver on AUS, but 27.8% of those with FLI ≥ 60 had normal liver on AUS. FLI has striking agreement with SteatoTest and moderate agreements with AUS or HRI. However, if intermediate values are excluded FLI has high diagnostic value vs AUS.


Impact of microvascular obstruction on semiautomated techniques for quantifying acute and chronic myocardial infarction by cardiovascular magnetic resonance.
The four most promising semiautomated techniques (5-SD, 6-SD, Otsu and the full width half maximum (FWHM)) were compared in paired acute and follow-up cardiovascular magnetic resonance (CMR), taking into account the impact of microvascular obstruction (MVO) and using automated extracellular volume fraction (ECV) maps for reference. Furthermore, their performances on the acute scan were compared against manual myocardial infarct (MI) size to predict adverse left ventricular (LV) remodelling (≥20% increase in end-diastolic volume). 40 patients with reperfused ST segment elevation myocardial infarction (STEMI) with a paired acute (4±2 days) and follow-up CMR scan (5±2 months) were recruited prospectively. All CMR analysis was performed on CVI42. Using manual MI size as the reference standard, 6-SD accurately quantified acute (24.9±14.0%LV, p=0.81, no bias) and chronic MI size (17.2±9.7%LV, p=0.88, no bias). The performance of FWHM for acute MI size was affected by the acquisition sequence used. Furthermore, FWHM underestimated chronic MI size in those with previous MVO due to the significantly higher ECV in the MI core on the follow-up scans previously occupied by MVO (82 (75-88)% vs 62 (51-68)%, p<0.001). 5-SD and Otsu were precise but overestimated acute and chronic MI size. All techniques were performed with high diagnostic accuracy and equally well to predict adverse LV remodelling. 6-SD was the most accurate for acute and chronic MI size and should be the preferred semiautomatic technique in randomised controlled trials. However, 5-SD, FWHM and Otsu could also be used when precise MI size quantification may be adequate (eg, observational studies).


A classical description of subnanometer resolution by atomic features in metallic structures.
Recent experiments have evidenced sub-nanometer resolution in plasmonic-enhanced probe spectroscopy. Such a high resolution cannot be simply explained using the commonly considered radii of metallic nanoparticles on plasmonic probes. In this contribution the effects of defects as small as a single atom found on spherical plasmonic particles acting as probing tips are investigated in connection with the spatial resolution provided. The presence of abundant edge and corner sites with atomic scale dimensions in crystalline metallic nanoparticles is evident from transmission electron microscopy (TEM) images. Electrodynamic calculations based on the Finite Element Method (FEM) are implemented to reveal the impact of the presence of such atomic features in probing tips on the lateral spatial resolution and field localization. Our analysis is developed for three different configurations, and under resonant and non-resonant illumination conditions, respectively. Based on this analysis, the limits of field enhancement, lateral resolution and field confinement in plasmon-enhanced spectroscopy and microscopy are inferred, reaching values below 1 nanometer for reasonable atomic sizes.


Recognizing the tenascin-X deficient type of Ehlers-Danlos syndrome: a cross-sectional study in 17 patients.
The tenascin-X (TNX) deficient type Ehlers-Danlos syndrome (EDS) is similar to the classical type of EDS. Because of the limited awareness among geneticists and the challenge of the molecular analysis of the TNXB gene, the TNX-deficient type EDS is probably to be under diagnosed. We therefore performed an observational, cross-sectional study. History and physical examination were performed. Results of serum TNX measurements were collected and mutation analysis was performed by a combination of next-generation sequencing (NGS), Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). Included were 17 patients of 11 families with autosomal recessive inheritance and childhood onset. All patients had hyperextensible skin without atrophic scarring. Hypermobility of the joints was observed in 16 of 17 patients. Deformities of the hands and feet were observed frequently. TNX serum level was tested and absent in 11 patients (seven families). Genetic testing was performed in all families; 12 different mutations were detected, most of which are suspected to lead to non-sense mRNA mediated decay. In short, patients with the TNX-deficient type EDS typically have generalized joint hypermobility, skin hyperextensibility and easy bruising. In contrast to the classical type, the inheritance pattern is autosomal recessive and atrophic scarring is absent. Molecular analysis of TNXB in a diagnostic setting is challenging.


Metallothionein expression and synthesis in the testis of the lizard Podarcis sicula under natural conditions and following estrogenic exposure.
Metallothionein (MT) is the main protein involved in the homeostasis of metallic micronutrients and in cellular defence against heavy metals and reactive oxygen species. Found in almost all vertebrate tissues, MT presence and localization in the testis has been controversial. In the present study, by using in situ hybridization and immunohistochemical analysis we assessed the localization of both MT transcript and protein in Podarcis sicula testes during two different phases of the reproductive cycle: the autumnal resumption and the spring-early summer mating period. In addition, with the same methodological approach, we verified the effect of estradiol-17ß and nonylphenol, a potent xenoestrogen, on MT expression and synthesis. These results, the first collected in a non-mammalian oviparous vertebrate, demonstrated that the expression profile of MT mRNA and protein changes during the reproductive cycle. In the fall resumption, MT transcripts are absent in spermatogonia and present in all the other cells of tubules, including spermatozoa; vice versa, the MT protein is evident only in spermatozoa and somatic cells. In the mating period, both MT transcripts and proteins are present in spermatogonia, spermatocytes and spermatids, whereas in the spermatozoa only the proteins are detected, thus suggesting that the MTs translated in the earlier germinal stages are stored up to spermatozoa. Results also demonstrated that in lizard testis the expression of MT gene undergoes a cell-specific regulation after estrogenic exposure; the possible role and the mechanism by which this regulation occurs have been discussed.


A Digital Pornography Literacy Resource Co-Designed With Vulnerable Young People: Development of "The Gist".
The impact of viewing pornography at a young age on the sexual health of subgroups of young people is an important public health issue. However, the topic is complex and extremely sensitive, and best practices for research and harm reduction are yet to be defined. Drawing on cross-disciplinary approaches, such as co-design, is one way to achieve a better understanding of the issue among vulnerable young people and to create needs-based and evidence-informed digital resources to promote pornography literacy. The objective of this study was to co-design a relevant, usable, and acceptable digital prototype to address the pornography literacy needs of vulnerable young people. In total, 17 young people aged between 14 and 23 years who were engaged in youth services programs or alternative education programs were recruited to participate in 4 co-design workshops with a multidisciplinary design team. Although the participants could identify problems with pornography and critique its messages, they lacked the information to understand alternative healthy attitudes and behaviors. A digital resource that provides detailed and practical information about sex, sexual ethics, and relationships may help vulnerable young people to identify and contrast with any problematic messages they receive from both pornography and society. Embedding this information with pornography literacy messages may be a more effective way of addressing underlying attitudes. Acknowledging information-seeking patterns and leveraging user interaction patterns from commonly used digital platforms among users may enhance engagement with resources. Importantly, digital platforms are perceived among this group as a source of anonymous secondary information but would not be organically accessed among this group without face-to-face conversations as an access point. This paper highlights the potential for pornography literacy to be embedded within real and practical information about having sex, navigating sexuality, and healthy relationships. The study findings include important recommendations for the conceptualization of digital pornography literacy programs and opportunities for cross-disciplinary co-design research to address complex and emerging health issues.


Deletions and amplifications of tandemly arranged ribosomal 5S genes internal to a P element occur at a high rate in a dysgenic context.
We observed unusual kinds of rearrangements within tandemly clustered 5S genes internal to a P element in dysgenic context. Rearranged P transposons, initially containing eight 5S genes, were found to display discrete numbers of 5S genes, from 4 up to 17 units. Precise deletions and amplifications occurred at a high rate (40%), at both original and new insertion sites. These events can be explained by a "cut and paste" transposition model. Possible links between rearrangements due to dysgenic-like processes and concerted evolution are discussed.


Gait speed at usual pace as a predictor of adverse outcomes in community-dwelling older people an International Academy on Nutrition and Aging (IANA) Task Force.
The use of a simple, safe, and easy to perform assessment tool, like gait speed, to evaluate vulnerability to adverse outcomes in community-dwelling older people is appealing, but its predictive capacity is still questioned. The present manuscript summarises the conclusions of an expert panel in the domain of physical performance measures and frailty in older people, who reviewed and discussed the existing literature in a 2-day meeting held in Toulouse, France on March 12-13, 2009. The aim of the IANA Task Force was to state if, in the light of actual scientific evidence, gait speed assessed at usual pace had the capacity to identify community-dwelling older people at risk of adverse outcomes, and if gait speed could be used as a single-item tool instead of more comprehensive but more time-consuming assessment instruments. A systematic review of literature was performed prior to the meeting (Medline search and additional pearling of reference lists and key-articles supplied by Task Force members). Manuscripts were retained for the present revision only when a high level of evidence was present following 4 pre-selected criteria: a) gait speed, at usual pace, had to be specifically assessed as a single-item tool, b) gait speed should be measured over a short distance, c) at baseline, participants had to be autonomous, community-dwelling older people, and d) the evaluation of onset of adverse outcomes (i.e. disability, cognitive impairment, institutionalisation, falls, and/or mortality) had to be assessed longitudinally over time. Based on the prior criteria, a final selection of 27 articles was used for the present manuscript. Gait speed at usual pace was found to be a consistent risk factor for disability, cognitive impairment, institutionalisation, falls, and/or mortality. In predicting these adverse outcomes over time, gait speed was at least as sensible as composite tools. Although more specific surveys needs to be performed, there is sufficient evidence to state that gait speed identifies autonomous community-dwelling older people at risk of adverse outcomes and can be used as a single-item assessment tool. The assessment at usual pace over 4 meters was the most often used method in literature and might represent a quick, safe, inexpensive and highly reliable instrument to be implemented.


The role of environmental biotechnology in exploring, exploiting, monitoring, preserving, protecting and decontaminating the marine environment.
In light of the Marine Strategy Framework Directive (MSFD) and the EU Thematic Strategy on the Sustainable Use of Natural Resources, environmental biotechnology could make significant contributions in the exploitation of marine resources and addressing key marine environmental problems. In this paper 14 propositions are presented focusing on (i) the contamination of the marine environment, and more particularly how to optimize the use of biotechnology-related tools and strategies for predicting and monitoring contamination and developing mitigation measures; (ii) the exploitation of the marine biological and genetic resources to progress with the sustainable, eco-compatible use of the maritime space (issues are very diversified and include, for example, waste treatment and recycling, anti-biofouling agents; bio-plastics); (iii) environmental/marine biotechnology as a driver for a sustainable economic growth.


Karyology of the Atlantic forest rodent Juliomys (Cricetidae): A new karyotype from southern Brazil.
Juliomys is a small rodent from the family Cricetidae which inhabits the Atlantic forest and forests from Argentina to eastern Brazil. The three species recognized so far have different karyotypes. In this paper, we describe a new karyotype with 2n = 32, FN = 48 found in Juliomys specimens from a high-altitude area in the Atlantic forest of southern Brazil. The karyotype was analyzed after G- and C-banding and silver staining of the nucleolus organizer regions (Ag-NOR) and its G-banding patterns were compared with those of the newly described species Juliomys ossitenuis (2n = 20, FN = 36). The 2n = 32 karyomorph presented peculiar features and was very different from those of the other species of the genus: J. pictipes (2n = 36, FN = 34), J. rimofrons (2n = 20, FN = 34) and J. ossitenuis (2n = 20, FN = 36). Differences were mostly due to centric and tandem fusions, pericentric inversion and loss of heterochromatin. The karyotype represents a powerful tool to differentiate Juliomys species and our data suggest that the karyotype described herein belongs to a new species.


Lead Optimization in Discovery Drug Metabolism and Pharmacokinetics/Case study: The Hepatitis C Virus (HCV) Protease Inhibitor SCH 503034.
Lead optimization using drug metabolism and pharmacokinetics (DMPK) parameters has become one of the primary focuses of research organizations involved in drug discovery in the last decade. Using a combination of rapid in vivo and in vitro DMPK screening procedures on a large array of compounds during the lead optimization process has resulted in development of compounds that have acceptable DMPK properties. In this review, we present a general screening paradigm that is currently being used as part of drug discovery at Schering-Plough and we describe a case study using the Hepatitis C Virus (HCV) protease inhibitor program as an example. By using the DMPK optimization tools, a potent HCV protease inhibitor, SCH 503034, was selected for development as a candidate drug.


An NMR blood test for cancer: a critical assessment.
An evaluation of the reproducibility and accuracy of the NMR human blood test for cancer described by Fossel, E. T., Carr, J. M. and McDonagh, J., (New England Journal of Medicine 315, 1369-1376) in 1986 has been conducted jointly at the National Cancer Institute-Frederick Cancer Research Facility, Frederick, MD (NCI-FCRF) and the National Research Council, Ottawa, Canada (NRC). The influences on the test of the following were studied: (a) subject fasting; (b) sample collection, storage and handling; (c) use of plasma or serum; (d) variations of test results from the same individual with time; (e) NMR observation parameters including field strength and temperature; and (f) variations in obtaining the Fossel Index (FI) (a number defined by Fossel and co-workers as the average of the widths at half height of the regions in the NMR spectrum of human plasma at 1.3 and 0.88 ppm) by different people from the same plotted spectrum. This test was found to be reproducible but not accurate for screening a general asymptomatic population. The accuracy is defined in terms of the sensitivity, specificity, and predictive values of the test. The accuracy of the test results from our laboratories is compared with the accuracies from other laboratories including Fossel's. The correlation of the Fossel Index with total triglyceride content in the serum has been confirmed by analysing blood components using the following technologies: KBr density gradient centrifugation, high resolution agarose gel electrophoresis, high performance gel permeation chromatography, and chemical analysis.


No Difference Between Trabecular Metal Cones and Femoral Head Allografts in Revision TKA: Minimum 5-year Followup.
Encouraging clinical results have been reported with the use of femoral head structural allografts and, more recently, trabecular metal cones for the management of large structural defects of the femur and tibia during revision total knee arthroplasty (TKA). However, to our knowledge, there are no published studies comparing these two techniques. Compared with bulk allografts, do trabecular metal cones result in (1) better validated outcomes scores; (2) a lower risk of loosening or revision at 5 years; and (3) fewer surgical complications when used for the management of bone loss in revision TKA? Between 2002 and 2008, three surgeons performed 450 TKA revisions, 45 (10%) of which were performed using augmentation of host bone; in those, femoral head allograft was used in 30 (75%) and trabecular metal cones in 15 (25%). From 2002 to 2007, femoral head allografts were used in all patients (28 patients); from 2007 to 2008, trabecular metal augments were used in all patients. There was a period of 1 year (16 knees) in which there was some overlap; during that time, femoral head structural allografts were used in cases in which we were unable to fit the defect or achieve adequate stability with trabecular metal cones. Followup was at a mean of 9 years (range, 5-12 years). No patients were lost to followup. Knee function and quality of life were assessed using the Oxford Knee Score, WOMAC, SF-12, and the UCLA activity score. Radiographs were assessed for signs of loosening. Surgical complications included superficial or deep infections, iatrogenic fractures, symptomatic deep venous thromboses or pulmonary emboli, and blood loss requiring transfusion; these were obtained from our database and from review of patients' charts. The mean Oxford Knee Score in the allograft and trabecular metal cone groups was 91 (SD 10) and 91 (SD 14), respectively (95% confidence interval [CI], 88-94; p = 0.29). Mean WOMAC scores were 94 (SD 10) and 92 (SD 14), respectively (95% CI, 80-105; p = 0.52) and mean UCLA scores were 6 (SD 1.2) and 6 (SD 1.5), respectively (95% CI, 4-8; p = 0.49). Five- and 10-year survivorship of the allografts was 93% (95% CI, 77-98) and 93% (95% CI, 77-99), respectively. Survivorship at a mean of 5 years in the trabecular metal cones group was 91% (95% CI, 56-98). With the numbers available, there were no differences between the groups in terms of the frequency of surgical complications (3% [one of 30] versus 7% [one of 15]; odds ratio, 0.5; p = 0.632). With the numbers available, we found no difference in pain, function, or repeat revision when comparing femoral head allografts and trabecular metal cones for severe bone defects during revision TKA. However, we used allografts for the larger bone defects. Based on these results, we believe that femoral head allografts and trabecular metal cones can both be used for the management of Anderson Orthopaedic Research Institute Types 2 and 3 defects. Future multicenter studies are required with larger numbers, cost analyses, and a longer duration of followup. Level III, therapeutic study.


Intracranial pressure waveform analysis during rest and suctioning.
Cerebral compliance is a measure of cerebral adaptability to increases in volume within the intracranial space and an indicator of risk for neurological deterioration. However, no direct measurement of compliance exists in clinical practice to guide nursing care or treatment decisions. Current use of mean intracranial pressure (MICP) and gross morphological intracranial pressure waveform (ICPW) analysis have great variability in predicting outcomes. The purpose of this review and pilot study was to evaluate the effects of suctioning on MICP and other measures estimating cerebral compliance derived from analysis of ICPW on patient outcome. We analyzed arterial blood pressure waveforms (ABPWs), ICPWs, and respiratory cycle variations using Fourier Transform analysis, to explore the potential benefits of studying ICPWs across single cardiac and respiratory cycles using linear modeling and calculation of correlation coefficients. ABPWs, ICPWs, and MICP were measured over individual cardiac cycles across multiple respiratory phases in five critically ill neurological patients. Both direct and derived ICP measures, including Fourier analysis of ABP and ICP and the cross-transform between ABP and ICP, were correlated with patient outcome. This more complex waveform analysis of individual ABPW and ICPW together, and derived measures during both single cardiac and respiratory cycles, may provide information relevant to cerebral compliance and patient outcomes. Pending confirmation with additional data sets, this technique may be a useful real-time clinical tool to provide a measure of compliance and risk of neurological deterioration for clinicians.


No effect of physiological concentrations of glucagon-like peptide-2 on appetite and energy intake in normal weight subjects.
To examine the effect of a GLP-2 infusion on appetite sensations and ad libitum energy intake in healthy, normal weight humans. The experiment was performed in a randomised, blinded, and placebo-controlled crossover design. Placebo or GLP-2 was infused (infusion rate of 25 pmol/kg body wth) for 4.5 h. A total of 18 healthy, normal weight young subjects participated; eight women and 10 men. During the infusion, subjects recorded their appetite sensations every 30 min using visual analogue scales, and blood was sampled frequently. After 2 h of infusion, an ad libitum meal, consisting of sandwiches, was served. The concentration of GLP-2 was significantly higher during the GLP-2 infusion compared with placebo (P<0.0001) and increased further in both conditions in response to the meal. Neither appetite sensations, nor palatability of the test meals, or energy intake were different on the two occasions. Glucose, GLP-1, insulin, and GIP responses were also unaffected by the infusion, whereas glucagon levels were higher during the GLP-2 treatment (P<0.05). Circulating GLP-2 in physiological concentrations does not seem to play a significant role in human appetite regulation.


Absence of tumor necrosis factor-alpha does not affect motor neuron disease caused by superoxide dismutase 1 mutations.
An increase in the expression of the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) has been observed in patients with amyotrophic lateral sclerosis (ALS) and in the mice models of the disease. TNF-alpha is a potent activator of macrophages and microglia and, under certain conditions, can induce or exacerbate neuronal cell death. Here, we assessed the contribution of TNF-alpha in motor neuron disease in mice overexpressing mutant superoxide dismutase 1 (SOD1) genes linked to familial ALS. This was accomplished by the generation of mice expressing SOD1(G37R) or SOD1(G93A) mutants in the context of TNF-alpha gene knock out. Surprisingly, the absence of TNF-alpha did not affect the lifespan or the extent of motor neuron loss in SOD1 transgenic mice. These results provide compelling evidence indicating that TNF-alpha does not directly contribute to motor neuron degeneration caused by SOD1 mutations.


Detection of M. tuberculosis using DNA chips combined with an image analysis system.
To develop a packaged DNA chip assay (the DR. MTBC Screen assay) for direct detection of the Mycobacterium tuberculosis complex. We described a DNA chip assay based on the IS6110 gene that can be used for the detection of M. tuberculosis complex. Probes were spotted onto the polystyrene strips in the wells of 96-well microtitre plates and used for hybridisation with biotin-labelled amplicon to yield a pattern of visualised positive spots. The plate image was scanned, analysed and interpreted automatically. The results corresponded well with those obtained by conventional culture as well as clinical diagnosis, with sensitivity and specificity rates of respectively 83.8% and 94.2%, and 84.6% and 96.3%. We conclude that the DR. MTBC Screen assay can detect M. tuberculosis complex rapidly in respiratory specimens, readily adapts to routine work and provides a flexible choice to meet different cost-effectiveness and automation needs in TB-endemic countries. The cost for reagents is around US$10 per sample.


Perception of smooth and perturbed vection in short-duration microgravity.
Successful adaptation to the microgravity environment of space and readaptation to gravity on earth requires recalibration of visual and vestibular signals. Recently, we have shown that adding simulated viewpoint oscillation to visual self-motion displays produces more compelling vection (despite the expected increase in visual-vestibular conflict experienced by stationary observers). Currently, it is unclear what role adaptation to gravity might play in this oscillation-based vection advantage. The vection elicited by optic flow displays simulating either smooth forward motion or forward motion perturbed by viewpoint oscillation was assessed before, during and after microgravity exposure in parabolic flight. During normal 1-g conditions subjects experienced significantly stronger vection for oscillating compared to smooth radial optic flow. The magnitude of this oscillation enhancement was reduced during short-term microgravity exposure, more so for simulated interaural (as opposed to spinal) axis viewpoint oscillation. We also noted a small overall reduction in vection sensitivity post-flight. A supplementary experiment found that 1-g vection responses did not vary significantly across multiple testing sessions. These findings: (i) demonstrate that the oscillation advantage for vection is very stable and repeatable during 1-g conditions and (ii) imply that adaptation or conditioned responses played a role in the post-flight vection reductions. The effects observed in microgravity are discussed in terms of the ecology of terrestrial locomotion and the nature of movement in microgravity.


Electrogenic sodium absorption in rabbit cecum in vitro.
Regional variations in the ion transport properties of the colon may have significant physiological and pathophysiological implications. However, only limited studies have been performed in cecum, which comprises 50% of the macrosurface of the rabbit colon. In vitro under short-circuit conditions, cecum actively absorbed Na and Cl (JnetNa = 5.6 +/- 0.3, JnetCl = 1.5 +/- 0.3 mu eq.cm-2.h-1) with a short-circuit current (Isc) of 6.29 +/- 0.2 mu eq.cm-2.h-1.Cl substitution with sulfate decreased both JnetNa and Isc by 1.3 mu eq/cm2.h-1.HCO3 removal decreased both JnetNa and Isc 3.3 mu eq.cm-2.h-1. This effect was due primarily to removal of serosal HCO3. There was both a linear correlation between JNanet and Isc (r = 0.845) and a concentration-dependent stimulation of Isc by increasing [Na] in the bathing media. However, 10(-4) M amiloride did not significantly alter either Isc or JnetNa. In contrast, 10(-4) M phenamil, an amiloride analogue highly specific for the Na channel, significantly blocked both Isc and JnetNa. The sulfhydryl reagent PCMBS increased Isc; this response was reversed by phenamil. Electrogenic Cl secretion was stimulated by 1 mM theophylline, 10(-4) M 8BrcAMP and 10(-4) M 8BrcGMP. None of the secretagogues inhibited JnetNa. Epinephrine (5.5 microM) increased JnetNa from 5.9 +/- 1.3 to 7.8 +/- 1.1 (P = 0.02) and JnetCl from 0.1 +/- 1.2 to 2.0 +/- 0.8 (P NS) mu eq.cm-2.h-1. Studies of pH stat demonstrated an epinephrine-stimulated increase in Jm-sHCO3 without a change in Js-mHCO3. Thus, cecum exhibits a distinct type of electrogenic Na electrogenic Na absorption which is partially dependent on the presence of Cl and HCO3, not blocked by amiloride but by phenamil. Because of its large surface area and its novel mechanism of electrogenic Na transport, the cecum exerts an important regulatory role in colonic fluid and electrolyte balance.


Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC).
Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68-0.90, p = 5.59 × 10-4]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1, may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways.


Elucidation of carbon sources used for the biosynthesis of fatty acids and sterols in the trypanosomatid Leishmania mexicana.
Sterols are necessary for the growth of trypanosomatid protozoans; sterol biosynthesis is a potential target for the use and development of drugs to treat the diseases caused by these organisms. This study has used (14)C-labelled substrates to investigate the carbon sources utilized by promastigotes and amastigotes of Leishmania mexicana for the production of sterol [mainly ergosta-5,7,24(24(1))-trien-3beta-ol] and the fatty acid moieties of the triacylglycerol (TAG) and phospholipid (PL) of the organism. The isoprenoid precursor mevalonic acid (MVA) was incorporated into the sterols, and the sterol precursor squalene, by the promastigotes of L. mexicana. However, acetate (the precursor to MVA in most organisms) was a very poor substrate for sterol production but was readily incorporated into the fatty acids of TAG and PL. Other substrates (glucose, palmitic acid, alanine, serine and isoleucine), which are metabolized to acetyl-CoA, were also very poor precursors to sterol but were incorporated into TAG and PL and gave labelling patterns of the lipids similar to those of acetate. In contrast, the amino acid leucine was the only substrate to be incorporated efficiently into the squalene and sterol of L. mexicana promastigotes. Quantitative measurements revealed that at least 70-80% of the sterol synthesized by the promastigotes of L. mexicana is produced from carbon provided by leucine metabolism. Studies with the amastigote form of L. mexicana showed that in this case leucine was again the major sterol precursor, whereas acetate was utilized for fatty acid production.


Incorporating Patient-Reported Outcomes Into Health Care To Engage Patients And Enhance Care.
The provision of patient-centered care requires a health care environment that fosters engagement between patients and their health care team. One way to encourage patient-centered care is to incorporate patient-reported outcomes into clinical settings. Collecting these outcomes in routine care ensures that important information only the patient can provide is captured. This provides insights into patients' experiences of symptoms, quality of life, and functioning; values and preferences; and goals for health care. Previously embraced in the research realm, patient-reported outcomes have started to play a role in successful shared decision making, which can enhance the safe and effective delivery of health care. We examine the opportunities for using patient-reported outcomes to enhance care delivery and outcomes as health care information needs and technology platforms change. We highlight emerging practices in which patient-reported outcomes provide value to patients and clinicians and improve care delivery. Finally, we examine present and future challenges to maximizing the use of patient-reported outcomes in the clinic.


Cardiac resynchronisation therapy in patients with heart failure and a normal QRS duration: the RESPOND study.
To evaluate the clinical response to cardiac resynchronisation therapy (CRT) in patients with heart failure and a normal QRS duration (<120 ms). Single centre. 60 patients with heart failure and a normal QRS duration receiving optimal pharmacological treatment (OPT). Patients were randomly assigned to CRT (n=29) or to a control group (OPT, n=31). Cardiovascular magnetic resonance was used in order to avoid scar at the site of left ventricular (LV) lead deployment. The primary end point was a change in 6 min walking distance (6-MWD). Other measures included a change in quality of life scores (Minnesota Living with Heart Failure questionnaire) and New York Heart Association class. In 93% of implantations, the LV lead was deployed over non-scarred myocardium. At 6 months, the 6-MWD increased with CRT compared with OPT (p<0.0001), with more patients reaching a ≥25% increase (51.7% vs 12.9%, p=0.0019). Compared with OPT, CRT led to an improvement in quality-of-life scores (p=0.0265) and a reduction in NYHA class (p<0.0001). The composite clinical score (survival for 6 months free of heart failure hospitalisations plus improvement by one or more NYHA class or by ≥25% in 6-MWD) was better in CRT than in OPT (83% vs 23%, respectively; p<0.0001). Although no differences in total or cardiovascular mortality emerged between OPT and CRT, patients receiving OPT had a higher risk of death from pump failure than patients assigned to CRT (HR=8.41, p=0.0447) after a median follow-up of 677.5 days. CRT leads to an improvement in symptoms, exercise capacity and quality of life in patients with heart failure and a normal QRS duration. (ClinicalTrials.gov number, NCT00480051.).


A preliminary study on the mechanism of skeletal abnormalities in Turner syndrome using inducing pluripotent stem cells (iPS)- based disease models.
Osteoporosis represent one of main characteristics of Turner syndrome (TS), a rare diseases caused by aberrant deletion of X chromosomes, however, the underlying pathological mechanism remains unknown yet. In this study, we used pluripotent stem cells (iPSCs) derived from a Turner syndrome patient and a health control to induce functional osteoblasts and osteoclasts, in order to compare their difference in these two differentiation. We successfully produced functional osteoblasts and osteoclasts from iPSCs through embryoid bodies (EBs) and mesoderm stages, as demonstrated obvious mineralized nodules and multi-nuclear giant cells with positive tartrate-resistant acid phosphatase (TRAP) staining, and significant up-regulated differentiation marker genes. Interestingly, we found that there was no significant difference in phenotype and marker genes expression between osteoblasts from Turner syndrome and healthy control iPSCs. In contrast, Turner syndrome showed increased osteoclastogenesis compared to the healthy control indicating higher frequency of multi-nuclear TRAP staining cells and elevated osteoclast marker genes TRAP, MMP9, CA2, OSCAR. Therefore, our results suggest that the low bone density of Turner syndrome patients may be caused by aberrant osteoclast differentiation, and further investigation towards osteoclast function under Turner syndrome is deserved.


Day and night aspirin-induced gastric mucosal damage and protection by ranitidine in man.
The severity of gastric mucosal injury produced by aspirin (ASA) was endoscopically assessed during morning and evening studies in 10 healthy, male volunteers. In a randomized, double-blind design, subjects received either ASA (1300 mg) alone or ASA (1300 mg) plus Ranitidine (150 mg) or placebo tablets during morning and evening studies. Each subject had 3 morning and 3 evening studies. The severity of damage produced by ASA was assessed by counting the number of punctate mucosal hemorrhages observed in the gastric antrum and low-body. This study demonstrated (1) wide intersubject variability in the severity of damage produced by ASA (range of 47-1030 lesions/subject in morning studies), (2) significant protection against ASA-induced damage by Ranitidine and (3) significantly greater damage produced by ASA in the morning compared to the evening studies. Because evening acid secretory rates are higher and because ASA-induced damage is believed to be acid-dependent, this last observation was unexpected. It suggests mucosal resistance is higher in the evening and raises the possibility that there may be circadian variation in gastric mucosal resistance.


European guidelines on quality criteria for diagnostic radiographic images of the lumbar spine - an intra- and inter-observer reproducibility study.
The Commission of the European Communities has published guidelines to be used as a gold standard for quality assessment of diagnostic radiographic images. Image quality and radiation dose must be monitored and optimally balanced for diagnostic purposes on patients. The objective of the current study was to assess intra- and inter-observer reproducibility in less experienced observers using the proposed European Guidelines on Quality Criteria for Diagnostic Radiographic Images in a quality assessment of lumbar spine radiographs in primary chiropractic practice in Denmark. Two observers initially evaluated lumbar spine radiographs randomly selected from fifty chiropractic clinics, all connected to the national PACS server (KirPACS) in Denmark. All evaluations were performed twice by both observers using a four-week interval and for compliance with the European Quality Criteria for Diagnostic Radiographic Images. Inter- and intra-observer reproducibility was calculated using kappa statistics. In the interpretation of the kappa coefficient, the standards for strength of agreement reported by Landis and Koch were followed. The strength of the inter-observer agreement of general image quality at baseline ranged from moderate agreement (k = 0.47) to substantial agreement (k = 0.68). After four weeks, the inter-observer agreement still ranged from moderate agreement (k = 0.59) to substantial agreement (k = 0.71), but with increased agreement for both kappa coefficients. In relation to intra-observer agreement of general image quality, the strength for observer A ranged from moderate (k = 0.58) to substantial (k = 0.72) and the strength for observer B overall was substantial (k = 0.63-0.75). The European Guidelines on Quality Criteria for Diagnostic Radiographic Images are considered a gold-standard and used in a method for quality assurance within the Danish chiropractic profession. The inter-rater and intra-rater agreements in this study, using the CEC-criteria, were found mostly acceptable. With appropriate attention to clear understanding of the individual criteria and sufficient training, this method is found to be reliable, even using less experienced observers, to carry out Diagnostic Radiographic Image Quality-assurance in primary care settings.


Predictors of self reported adherence to antihypertensive medication in a nigerian population.
Poor adherence to anti-hypertensive medication severely compromises the effectiveness of treatment. The aim of this study was to determine the factors that are associated with poor adherence in a sample of hypertensive patients in Nsukka, Nigeria. The study employed a cross sectional, household survey to identify cases of hypertension in Nsukka. Adherence to antihypertensive medications was assessed on participants that have been previously detected of hypertension using patient's self report method. Study variables found to be correlated to adherence after adjusting for confounding variables were used in the multiple linear regression. Stepwise method was used to model the effect of predictor variables on adherence. A total of seven hundred and fifty-six (756) participants were screened for hypertension. Prevalence of hypertension in the study population was 21.1 %. Detection of high BP among the participants with raised blood pressure was 30 %. Mean self reported adherence to hypertension medication(s) was 70.7 % ± 37.9 %. Educational status, making medication(s) a habit and experience of side effects were independently correlated to adherence. Multiple linear regression showed that for every increase in educational status, adherence increased by 12.1%. Also making medication a habit increased adherence by 35.1 %. However, experience of side-effect decreased adherence by 20.1%. Higher educational status and forming a habit of taking medication regularly increased adherence to hypertension medications while experience of a side-effect decreased adherence to medication. These fac tors identified as correlates of self reported adherence could be used to design interventions to improve adherence to hypertension medications in Nigeria.


Construct Validity of Scores From the Connor-Davidson Resilience Scale in a Sample of Postsecondary Students With Disabilities.
Although theory posits a multidimensional structure of resilience, studies have supported a unidimensional solution for data obtained from the commonly used Connor-Davidson Resilience Scale (CD-RISC). This study investigated the latent structure of CD-RISC responses in a sample of postsecondary students with disabilities. Furthermore, the validity of CD-RISC scores was examined with respect to career optimism and well-being. The analyses were conducted using confirmatory factor analysis and exploratory structural equation modeling (ESEM). Results supported a bifactor-ESEM representation of the CD-RISC data that accounts for construct-relevant multidimensionality in scores due to the presence of general and specific factors and the fallibility of indicators as pure reflections of the constructs they measure. Although three specific factors showed meaningful residual specificity over and above the general factor, two specific factors were weakly defined with little meaningful residual specificity. However, these factors may retain some utility in the bifactor-ESEM model insofar as they control for limited levels of residual covariance in items. Evidence was also obtained for relations of the general and substantively interpretable specific factors with career optimism and well-being. The results of the study provide validation data for the CD-RISC and clarify recent research converging on seemingly disparate unidimensional and multidimensional solutions.


Naturally occurring disk herniation in dogs: an opportunity for pre-clinical spinal cord injury research.
Traumatic spinal cord injuries represent a significant source of morbidity in humans. Despite decades of research using experimental models of spinal cord injury to identify candidate therapeutics, there has been only limited progress toward translating beneficial findings to human spinal cord injury. Thoracolumbar intervertebral disk herniation is a naturally occurring disease that affects dogs and results in compressive/contusive spinal cord injury. Here we discuss aspects of this disease that are analogous to human spinal cord injury, including injury mechanisms, pathology, and metrics for determining outcomes. We address both the strengths and weaknesses of conducting pre-clinical research in these dogs, and include a review of studies that have utilized these animals to assess efficacy of candidate therapeutics. Finally, we consider a two-species approach to pre-clinical data acquisition, beginning with a reproducible model of spinal cord injury in the rodent as a tool for discovery with validation in pet dogs with intervertebral disk herniation.


Absence of detectable arsenate in DNA from arsenate-grown GFAJ-1 cells.
A strain of Halomonas bacteria, GFAJ-1, has been claimed to be able to use arsenate as a nutrient when phosphate is limiting and to specifically incorporate arsenic into its DNA in place of phosphorus. However, we have found that arsenate does not contribute to growth of GFAJ-1 when phosphate is limiting and that DNA purified from cells grown with limiting phosphate and abundant arsenate does not exhibit the spontaneous hydrolysis expected of arsenate ester bonds. Furthermore, mass spectrometry showed that this DNA contains only trace amounts of free arsenate and no detectable covalently bound arsenate.


Grain legume seed systems for smallholder farmers: Perspectives on successful innovations.
Grain legumes are nutritionally important components of smallholder farming systems in sub-Saharan Africa and Asia. Unfortunately, limited access to quality seed of improved varieties at affordable prices due to inadequate seed systems has reduced their contribution to improving nutrition and reducing poverty in these regions. This paper analyses four seed systems case studies: chickpea in Ethiopia and Myanmar; cowpea in Nigeria; and tropical grain legumes in Nigeria, Tanzania and Uganda highlighting outcomes, lessons learned, and the enabling factors which supported the successful innovations. All four case studies highlighted at least some of the following outcomes: increased adoption of improved varieties and area planted; increased productivity and income to farmers; improved market access and growth; and significant national economic benefits. Important lessons were learned including the value of small seed packets to reach many farmers; the value of innovative partnerships; capacity building of value chain actors; and continuity and coherence of funding through Tropical Legumes projects II and III and the recently funded Accelerated Varietal Improvement and Seed Delivery of Legumes and Cereals in Africa (AVISA) project. Successful adoption of innovations depends not just on the right technologies but also on the enabling environment. The case studies clearly showed that market demand was correctly identified, establishment of successful partners and institutional linkages overcame constraints in production and delivery of improved seed to smallholders, and fostered conducive policies supported national seed systems. All were integral to seed system viability and sustainability. It is hoped that these examples will provide potential models for future grain legume seed systems efforts. In addition, the analysis identified a number of areas that require further research.


Clinical signs, diagnosis and treatment of duodenal ileus in cattle.
The clinical signs, changes in blood and rumen fluid, findings at laparotomy, therapy and course of disease of 23 cows with obstruction or compression of the duodenum are described. The duodenum was obstructed by a phytobezoar in 14 cows and by a blood clot in one cow. In eight cows, the duodenum was compressed by and adhered to a liver abscess. The most important clinical findings included moderate to severe disturbance in the general behaviour and attitude, markedly reduced gastrointestinal activity, no or greatly reduced defaecation and abomasal reflux with metabolic alkalosis. Ten cows were slaughtered after clinical examination or exploratory laparotomy. In 13 cows, the phytobezoar was compressed manually to facilitate normal elimination, and if this was not possible, the phytobezoar was removed by enterotomy. Postoperative therapy consisted of intravenous administration of a solution containing sodium chloride and glucose, potassium chloride and intramuscular administration of metoclopramide, procaine penicillin and flunixin meglumine for three to five days. Two of the treated cows were slaughtered a few days postoperatively. There was a rapid improvement in the remaining 11 cows, and general condition, appetite and defaecation returned to normal within a short time.


Physically-based in silico light sheet microscopy for visualizing fluorescent brain models.
We present a physically-based computational model of the light sheet fluorescence microscope (LSFM). Based on Monte Carlo ray tracing and geometric optics, our method simulates the operational aspects and image formation process of the LSFM. This simulated, in silico LSFM creates synthetic images of digital fluorescent specimens that can resemble those generated by a real LSFM, as opposed to established visualization methods producing visually-plausible images. We also propose an accurate fluorescence rendering model which takes into account the intrinsic characteristics of fluorescent dyes to simulate the light interaction with fluorescent biological specimen. We demonstrate first results of our visualization pipeline to a simplified brain tissue model reconstructed from the somatosensory cortex of a young rat. The modeling aspects of the LSFM units are qualitatively analysed, and the results of the fluorescence model were quantitatively validated against the fluorescence brightness equation and characteristic emission spectra of different fluorescent dyes. Modelling and simulation.


Enteropathogenic Escherichia coli O125:H6 triggers attaching and effacing lesions on human intestinal biopsy specimens independently of Nck and TccP/TccP2.
Typical enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC) employ either Nck, TccP/TccP2, or Nck and TccP/TccP2 pathways to activate the neuronal Wiskott-Aldrich syndrome protein (N-WASP) and to trigger actin polymerization in cultured cells. This phenotype is used as a marker for the pathogenic potential of EPEC and EHEC strains. In this paper we report that EPEC O125:H6, which represents a large category of strains, lacks the ability to utilize either Nck or TccP/TccP2 and hence triggers actin polymerization in vitro only inefficiently. However, we show that infection of human intestinal biopsies with EPEC O125:H6 results in formation of typical attaching and effacing lesions. Expression of TccP in EPEC O125:H6, which harbors an EHEC O157-like Tir, resulted in efficient actin polymerization in vitro and enhanced colonization of human intestinal in vitro organ cultures with detectable N-WASP and electron-dense material at the site of bacterial adhesion. These results show the existence of a natural category of EPEC that colonizes the gut mucosa using Nck- and TccP-independent mechanisms. Importantly, the results highlight yet again the fact that conclusions made on the basis of in vitro cell culture models cannot be extrapolated wholesale to infection of mucosal surfaces and that the ability to induce actin polymerization on cultured cells should not be used as a definitive marker for EPEC and EHEC virulence.


[Natural history of gallbladder cancer. Analysis of biopsy specimens].
There is scarcity of knowledge about the development of gallbladder cancer. To study the features of development and progression of gallbladder cancer. Review of histopathological studies of gallbladder obtained in 25,971 cholecytectomies performed in patients aged 45+/- 16 years, 79% females, between 1993 and 2004. Among these, 210 had a dysplasia not associated to cancer and 1,039 had a gallbladder cancer Clinical and morphological parameters of preneoplastic and neoplastic lesions were analyzed. Ninety five percent of patients were followed. All cases of dysplasia were incidental findings. Metaplasia, dysplasia and carcinoma in situ were present in the adjacent mucosa in 66%, 81% y 69% of gallbladder carcinomas, respectively. Twenty five percent of gallbladders studied were carcinomas (mucous carcinoma in 18% and muscular carcinoma in 7%). Ninety two percent of cases had chronic inflammation in the gallbladder wall. Seventy two percent of mucous carcinomas were not detected macroscopically Five years survival of mucous carcinoma was 92%. There was an association between the intensity of the lesion and the age of the patients. The age difference between chronic cholecystitis and gallbladder cancer was 11 years for women and nine for men. From a morphological standpoint, the period in which a dysplasia becomes a carcinoma is approximately 10 years.


Identification of a new epitope in uPAR as a target for the cancer therapeutic monoclonal antibody ATN-658, a structural homolog of the uPAR binding integrin CD11b (αM).
The urokinase plasminogen activator receptor (uPAR) plays a role in tumor progression and has been proposed as a target for the treatment of cancer. We recently described the development of a novel humanized monoclonal antibody that targets uPAR and has anti-tumor activity in multiple xenograft animal tumor models. This antibody, ATN-658, does not inhibit ligand binding (i.e. uPA and vitronectin) to uPAR and its mechanism of action remains unclear. As a first step in understanding the anti-tumor activity of ATN-658, we set out to identify the epitope on uPAR to which ATN-658 binds. Guided by comparisons between primate and human uPAR, epitope mapping studies were performed using several orthogonal techniques. Systematic site directed and alanine scanning mutagenesis identified the region of aa 268-275 of uPAR as the epitope for ATN-658. No known function has previously been attributed to this epitope Structural insights into epitope recognition were obtained from structural studies of the Fab fragment of ATN-658 bound to uPAR. The structure shows that the ATN-658 binds to the DIII domain of uPAR, close to the C-terminus of the receptor, corroborating the epitope mapping results. Intriguingly, when bound to uPAR, the complementarity determining region (CDR) regions of ATN-658 closely mimic the binding regions of the integrin CD11b (αM), a previously identified uPAR ligand thought to be involved in leukocyte rolling, migration and complement fixation with no known role in tumor progression of solid tumors. These studies reveal a new functional epitope on uPAR involved in tumor progression and demonstrate a previously unrecognized strategy for the therapeutic targeting of uPAR.


p53 mediated sensitization of squamous cell carcinoma of the head and neck to radiotherapy.
Radiation resistant squamous cell carcinoma of the head and neck cell line JSQ-3 carries a mutant form of tumor suppressor gene p53. Treatment of these cells with an adenoviral vector containing wild-type p53 (Av1p53) was able to inhibit their growth in vitro and in vivo while having no effect on normal cells. More significantly, introduction of wtp53 also reduced the radiation-resistance level of this cell line in vitro, in a viral dose-dependent manner. Furthermore, this radiosensitization also carried over to the in vivo situation where the response of JSQ-3 cell-induced mouse xenografts to radiotherapy was markedly enhanced after treatment with Av1p53. Complete, long-term regression of the tumors for up to 162 days was observed when a single dose of Av1p53 was administered in combination with ionizing radiation, demonstrating the effectiveness of this combination of gene therapy and conventional radiotherapy. This sensitization of tumors to radiation therapy by replacement of wtp53 could significantly decrease the rate of recurrence after radiation treatment. Since radiation is one of the most prevalent forms of adjunctive therapy for a variety of cancers, these results have great relevance in moving toward an improved cancer therapy.


Management of bone metastases in refractory prostate cancer--role of denosumab.
This article reviews the problem of bone disease in prostate cancer and the evolving role of the novel agent denosumab, a fully human monoclonal antibody that inhibits the receptor activator of nuclear factor-κB ligand, in suppressing bone resorption and offering bone protection in this disease. Prostate cancer frequently metastasizes to bone, and additionally its treatment with androgen deprivation leads to accelerated bone loss resulting in clinically relevant skeletal complications associated with disabling symptoms. Among the bone-targeting therapeutic strategies investigated for the prevention of bone complications, the potent bisphosphonate zoledronic acid has been the most widely used agent for bone protection in the past decade. Denosumab is the first among a new class of osteoclast-targeting agents to show superior efficacy in several clinical scenarios in both prostate and breast cancer, as well as in osteoporosis, but the focus of this review will be on its role in prostate cancer. The safety and efficacy of denosumab versus zoledronic acid was established in a randomized trial, demonstrating a delay in skeletal-related events in metastatic castration-resistant prostate cancer patients. This study led to the approval of denosumab in the US. The chief risks of denosumab were hypocalcemia and osteonecrosis of the jaw. Denosumab was also approved for fracture risk reduction in patients on androgen-deprivation therapy for nonmetastatic prostate cancer. Although denosumab extended bone metastasis-free survival in a Phase III trial in men with castration-resistant nonmetastatic prostate cancer to a statistically significant degree, a Food and Drug Administration committee found that the effect was not sufficiently clinically meaningful for regulatory approval, and the Food and Drug Administration issued a letter concurring with the committee's recommendation. The role of denosumab in prostate cancer will continue to evolve either as monotherapy or in combination with other bone-targeting strategies.


Peripheral joint inflammation in early onset spondyloarthritis is not specifically related to enthesitis.
A pivotal MRI study of knee arthritis indicated that enthesitis was more frequently observed in established spondyloartritis (SpA) than rheumatoid arthritis (RA). Subsequent MRI and ultrasound studies, however, failed to consistently demonstrate primary synovitis in RA versus primary enthesitis in SpA. Therefore, the current study aimed to reassess enthesitis versus synovitis in peripheral arthritis by a combined imaging and histopathological study in early untreated disease. MRI and mini-arthroscopic synovial biopsy sampling were performed in 41 patients with early untreated knee or ankle arthritis, who were diagnosed with SpA (n=13), RA (n=20) or crystal arthropathy (n=8) at follow-up. MRI evaluation of enthesitis and synovitis, and immunohistochemical characterisation of synovitis were performed by two observers blinded to diagnosis. MRI showed similar prevalence of perientheseal fluid/oedema (67% vs 75%), perientheseal bone marrow oedema (0% vs 10%) and entheseal enhancement (46% vs 47%) in SpA versus RA, respectively. The number and distribution of affected entheseal sites were not different between both diseases. The MRI synovitis score was significantly higher in SpA (median 1.4; IQR 1.1-1.5) compared with RA (median 0.5; IQR 0.0-1.3) (p=0.028). Synovial histopathology showed a numerical increase in infiltrating cells in SpA versus RA synovitis which reached significance for CD163 macrophages in the synovial sublining (p=0.030). There were no differences compared with the crystal arthropathy control group. Enthesitis on MRI is not a specific feature of peripheral arthritis in recent onset SpA versus RA. Synovitis is prominent in both diseases as evaluated by MRI and immunohistochemistry.


How to optimize hepatitis C virus treatment impact on life years saved in resource-constrained countries.
In resource-constrained countries where the prevalence of hepatitis C virus (HCV) disease is usually high, it is important to know which population should be treated first in order to increase treatment effectiveness. The aim was to estimate the effectiveness of different HCV treatment eligibility scenarios in three different countries. Using a Markov model, we estimated the number of life-years saved (LYS) with different treatment eligibility scenarios according to fibrosis stage (F1-F4 or F3-4), compared to base case (F2-F4), at a constant treatment rate, of patients between 18 and 60 years of age, at stages F0/F1 to F4, without liver complications or coinfections, chronically infected by HCV, and treated with pegylated interferon (IFN)/ribavirin or more-efficacious therapies (i.e. IFN free). We conducted the analysis in Egypt (prevalence = 14.7%; 45,000 patients treated/year), Thailand (prevalence = 2.2%; 1,000 patients treated/year), and Côte d'Ivoire (prevalence = 3%; 150 patients treated/year). In Egypt, treating F1 patients in addition to ≥F2 patients (SE1 vs. SE0) decreased LYS by 3.9%. Focusing treatment only on F3-F4 patients increased LYS by 6.7% (SE2 vs. SE0). In Thailand and Côte d'Ivoire, focusing treatment only on F3-F4 patients increased LYS by 15.3% and 11.0%, respectively, compared to treating patients ≥F2 (ST0 and SC0, respectively). Treatment only for patients at stages F3-F4 with IFN-free therapies would increase LYS by 16.7% versus SE0 in Egypt, 22.0% versus ST0 in Thailand, and 13.1% versus SC0 in Côte d'Ivoire. In this study, we did not take into account the yearly new infections and the impact of treatment on HCV transmission. Our model-based analysis demonstrates that prioritizing treatment in F3-F4 patients in resource-constrained countries is the most effective scenario in terms of LYS, regardless of treatment considered.


How Should We Capture Health State Utility in Dementia? Comparisons of DEMQOL-Proxy-U and of Self- and Proxy-Completed EQ-5D-5L.
Dementia-specific and proxy-completed preference-based measures have been proposed for use in intervention studies involving people living in residential care, in instances where generic, self-reported preference-based measures have been deemed inappropriate. This study was conducted to investigate the construct validity, criterion validity, and responsiveness of DEMQOL-Proxy-U and of self- and proxy-completed EQ-5D-5L. The analysis used a 3-wave, individual-level data set of 1004 people living with dementia in residential care that included self-completed EQ-5D-5L and formal-carer and informal-carer proxy-completed EQ-5D-5L and DEMQOL-Proxy-U utility values, in addition to other nonutility cognitive measures (Functional Assessment Staging [FAST], Clinical Dementia Rating [CDR], Cohen-Mansfield Agitation Inventory [CMAI]) and health-related quality of life (HRQOL) measures (nursing home version of the Quality of Life with Alzheimer's disease scale [QOL-AD-NH], Quality of Life in Late-Stage Dementia [QUALID] scale). Construct validity, criterion validity, and responsiveness were assessed using correlation, Bland-Altman plots, and panel data regression models. Self-completed EQ-5D-5L failed to reflect clinically important differences and changes in FAST, CDR, and CMAI but did capture the resident's own view of HRQOL (QOL-AD-NH). As dementia severity increased, collection of EQ-5D-5L-proxy and DEMQOL-Proxy-U data was more feasible than collection of self-completed EQ-5D-5L. These formal-carer and informal-carer proxy measures also better reflected changes in FAST, CDR, and CMAI but did not capture the resident's own view of HRQOL (QOL-AD-NH), despite adequately capturing the proxy's own view of the resident's HRQOL (QUALID). This indicates discrepancies between a proxy's view and resident's view of the impact that tangible declines in health, cognition, or functional abilities have on HRQOL. The EQ-5D-5L-proxy and DEMQOL-Proxy-U were generally poor substitutes. Regardless of which proxy completed it, the EQ-5D-5L-proxy was typically more responsive than the DEMQOL-Proxy-U to changes in CDR, FAST, and CMAI, indicating that use of the DEMQOL-Proxy-U is not always justified. Disparities in the measurement properties of different utility measures mean that choices about how to measure utility in trials could affect economic evaluation outcomes and hence how resources are allocated for dementia care.


Electronic and vibronic contributions to two-photon absorption in donor-acceptor-donor squaraine chromophores.
Many squaraines have been observed to exhibit two-photon absorption at transition energies close to those of the lowest energy one-photon electronic transitions. Here, the electronic and vibronic contributions to these low-energy two-photon absorptions are elucidated by performing correlated quantum-chemical calculations on model chromophores that differ in their terminal donor groups (diarylaminothienyl, indolenylidenemethyl, dimethylaminopolyenyl, or 4-(dimethylamino)phenylpolyenyl). For squaraines with diarylaminothienyl and dimethylaminopolyenyl donors and for the longer examples of 4-(dimethylamino)phenylpolyenyl donors, the calculated energies of the lowest two-photon active states approach those of the lowest energy one-photon active (1B(u)) states. This is consistent with the existence of purely electronic channels for low-energy two-photon absorption (TPA) in these types of chromophores. On the other hand, for all squaraines containing indolinylidenemethyl donors, the calculations indicate that there are no low-lying electronic states of appropriate symmetry for TPA. Actually, we find that the lowest energy TPA transitions can be explained through coupling of the one-photon absorption (OPA) active 1B(u) state with b(u) vibrational modes. Through implementation of Herzberg-Teller theory, we are able to identify the vibrational modes responsible for the low-energy TPA peak and to reproduce, at least qualitatively, the experimental TPA spectra of several squaraines of this type.