Safety, tolerability, pharmacokinetics, and activity of the novel long-acting antimalarial DSM265: a two-part first-in-human phase 1a/1b randomised study.
DSM265 is a novel antimalarial that inhibits plasmodial dihydroorotate dehydrogenase, an enzyme essential for pyrimidine biosynthesis. We investigated the safety, tolerability, and pharmacokinetics of DSM265, and tested its antimalarial activity. Healthy participants aged 18-55 years were enrolled in a two-part study: part 1, a single ascending dose (25-1200 mg), double-blind, randomised, placebo-controlled study, and part 2, an open-label, randomised, active-comparator controlled study, in which participants were inoculated with Plasmodium falciparum induced blood-stage malaria (IBSM) and treated with DSM265 (150 mg) or mefloquine (10 mg/kg). Primary endpoints were DSM265 safety, tolerability, and pharmacokinetics. Randomisation lists were created using a validated, automated system. Both parts were registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12613000522718 (part 1) and number ACTRN12613000527763 (part 2). In part 1, 73 participants were enrolled between April 12, 2013, and July 14, 2015 (DSM265, n=55; placebo, n=18). In part 2, nine participants were enrolled between Sept 30 and Nov 25, 2013 (150 mg DSM265, n=7; 10 mg/kg mefloquine, n=2). In part 1, 117 adverse events were reported; no drug-related serious or severe events were reported. The most common drug-related adverse event was headache. The mean DSM265 peak plasma concentration (Cmax) ranged between 1310 ng/mL and 34 800 ng/mL and was reached in a median time (tmax) between 1·5 h and 4 h, with a mean elimination half-life between 86 h and 118 h. In part 2, the log10 parasite reduction ratio at 48 h in the DSM265 (150 mg) group was 1·55 (95% CI 1·42-1·67) and in the mefloquine (10 mg/kg) group was 2·34 (2·17-2·52), corresponding to a parasite clearance half-life of 9·4 h (8·7-10·2) and 6·2 h (5·7-6·7), respectively. The median minimum inhibitory concentration of DSM265 in blood was estimated as 1040 ng/mL (range 552-1500), resulting in a predicted single efficacious dose of 340 mg. Parasite clearance was significantly faster in participants who received mefloquine than in participants who received DSM265 (p<0·0001). The good safety profile, long elimination half-life, and antimalarial effect of DSM265 supports its development as a partner drug in a single-dose antimalarial combination treatment. Wellcome Trust, UK Department for International Development, Global Health Innovative Technology Fund, Bill & Melinda Gates Foundation.


Hyper-activated pro-inflammatory CD16 monocytes correlate with the severity of liver injury and fibrosis in patients with chronic hepatitis B.
Extensive mononuclear cell infiltration is strongly correlated with liver damage in patients with chronic hepatitis B virus (CHB) infection. Macrophages and infiltrating monocytes also participate in the development of liver damage and fibrosis in animal models. However, little is known regarding the immunopathogenic role of peripheral blood monocytes and intrahepatic macrophages. The frequencies, phenotypes, and functions of peripheral blood and intrahepatic monocyte/macrophage subsets were analyzed in 110 HBeAg positive CHB patients, including 32 immune tolerant (IT) carriers and 78 immune activated (IA) patients. Liver biopsies from 20 IA patients undergoing diagnosis were collected for immunohistochemical analysis. IA patients displayed significant increases in peripheral blood monocytes and intrahepatic macrophages as well as CD16(+) subsets, which were closely associated with serum alanine aminotransferase (ALT) levels and the liver histological activity index (HAI) scores. In addition, the increased CD16(+) monocytes/macrophages expressed higher levels of the activation marker HLA-DR compared with CD16(-) monocytes/macrophages. Furthermore, peripheral blood CD16(+) monocytes preferentially released inflammatory cytokines and hold higher potency in inducing the expansion of Th17 cells. Of note, hepatic neutrophils also positively correlated with HAI scores. These distinct properties of monocyte/macrophage subpopulations participate in fostering the inflammatory microenvironment and liver damage in CHB patients and further represent a collaborative scenario among different cell types contributing to the pathogenesis of HBV-induced liver disease.


Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis.
Interleukin-17A (IL-17A) is elaborated by the T helper 17 (T(H)17) subset of T(H) cells and exhibits potent proinflammatory properties in animal models of autoimmunity, including collagen-induced arthritis, experimental autoimmune encephalomyelitis, and experimental autoimmune uveitis. To determine whether IL-17A mediates human inflammatory diseases, we investigated the efficacy and safety of AIN457, a human antibody to IL-17A, in patients with psoriasis, rheumatoid arthritis, and chronic noninfectious uveitis. Patients with chronic plaque-type psoriasis (n = 36), rheumatoid arthritis (n = 52), or chronic noninfectious uveitis (n = 16) were enrolled in clinical trials to evaluate the effects of neutralizing IL-17A by AIN457 at doses of 3 to 10 mg/kg, given intravenously. We evaluated efficacy by measuring the psoriasis area and severity index (PASI), the American College of Rheumatology 20% response (ACR20) for rheumatoid arthritis, or the number of responders for uveitis, as defined by either vision improvement or reduction in ocular inflammation or corticosteroid dose. AIN457 treatment induced clinically relevant responses of variable magnitude in patients suffering from each of these diverse immune-mediated diseases. Variable response rates may be due to heterogeneity in small patient populations, differential pathogenic roles of IL-17A in these diseases, and the different involvement or activation of IL-17A-producing cells. The rates of adverse events, including infections, were similar in the AIN457 and placebo groups. These results support a role for IL-17A in the pathophysiology of diverse inflammatory diseases including psoriasis, rheumatoid arthritis, and noninfectious uveitis.


Effect of probucol on antioxidant properties of HDL in patients with heterozygous familial hypercholesterolemia.
High density lipoprotein (HDL) has multi-antiatherogenic effects such as antioxidation and anti-inflammation, in addition to being a key mediator of reverse cholesterol transport. Probucol, known as a lipid lowering drug, is also a potent antioxidant, but it decreases serum HDL cholesterol (HDL-C) levels. To elucidate the effect of probucol on antioxidant properties of HDL, we investigated the function of HDL derived from patients with heterozygous familial hypercholesterolemia (FH) who have been treated with probucol. Probucol-treated FH patients (n=21) showed a 47% reduction of serum HDL-C levels compared to probucol-untreated FH patients (n=15). High performance liquid chromatography (HPLC) analysis revealed that probucol diminished HDL particle size compared to the non-treated group. Antioxidant capacity of HDL was evaluated by its effect to protect reference LDL from oxidation induced in the presence of an oxidizing agent, AAPH. The HDL derived from the probucol-treated group demonstrated a significantly prolonged time to start oxidation by 112%, decreased the maximum oxidation rate by 14%, and lowered the maximum concentration of conjugated dienes formation by 15%. Furthermore, HDL-associated paraoxonase 1 (PON1) activity, but not platelet-activating factor acetyl-hydrolase (PAF-AH) correlated with these measurements of HDL anti-oxidative activity. Treatment with probucol in vitro and inhibition of PON1 activity demonstrated that probucol in HDL particles and increase of PON1 activity might largely contribute to the increase of HDL anti-oxidative activity. Probucol reduced HDL-C levels and HDL particle size in patients with heterozygous FH, while it concomitantly enhanced HDL anti-oxidative properties, possibly through increasing PON1 activity.


Regions of interest analysis in pharmacological fMRI: how do the definition criteria influence the inferred result?
Prior hypotheses in functional brain imaging are often formulated by constraining the data analysis to regions of interest (ROIs). In this context, this approach yields higher sensitivity than whole brain analyses, which could be particularly important in drug development studies and clinical decision making. Here we systematically examine the effects of different ROI definition criteria on the results inferred from a hypothesis-driven pharmacological fMRI experiment, with the aim of maximising sensitivity and providing a recommended procedure for similar studies. In order to achieve this, we compared different criteria for selecting both anatomical and functional ROIs. Anatomical ROIs were defined (i) specifically for each subject, (ii) at group level, and (iii) using a Talairach-like atlas, in order to assess the effects of inter-subject anatomical variability. Functional ROIs (fROIs) were defined, both for each subject and at group level, by (i) selecting the voxels with the highest Z-score from each study session, and (ii) selecting an inclusive union of significantly active voxels across all sessions. A single value was used to summarise the response within each ROI. For anatomical ROIs we used the mean of the parameter estimates (beta values) of either all voxels or the top 20% active voxels. For fROIs we used the mean beta value of all voxels constituting the ROI. The results were assessed in terms of the achieved sensitivity in detecting the experimental effect. The use of single-subject anatomical ROIs combined with a summary value calculated from the top 20% fraction of active voxels was the most reliable and sensitive approach for detecting the experimental effect. The use of fROIs from individual sessions introduced unacceptable biases in the results, while the use of union fROIs yielded a lower sensitivity than anatomical ROIs. For these reasons, fROIs should be employed with caution when it is not possible to make clear anatomical prior hypotheses.


Coffee, tea, and melanoma risk among postmenopausal women.
Laboratory research suggests that components in coffee and tea may have anticarcinogenic effects. Some epidemiologic studies have reported that women who consume coffee and tea have a lower risk for melanoma. We assessed coffee, tea, and melanoma risk prospectively in the Women's Health Initiative - Observational Study cohort of 66,484 postmenopausal women, followed for an average of 7.7 years. Coffee and tea intakes were measured through self-administered questionnaires at baseline and at year 3 of follow-up. Self-reported incident melanomas were adjudicated using medical records. Cox proportional hazard models were used to estimate risk, adjusting for covariates, with person-time accumulation until melanoma diagnosis (n=398), death, loss to follow-up, or through 2005. Daily coffee [hazard ratio (HR)=0.87, 95% confidence interval (CI) 0.68-1.12] and tea (HR=1.03, 95% CI 0.81-1.31) intakes were not significantly associated with melanoma risk compared with nondaily intake of each beverage. No significant trends were observed between melanoma risk and increasing intakes of coffee (P for trend=0.38) or tea (P for trend=0.22). Women who reported daily coffee intake at both baseline and year 3 had a significantly decreased risk compared with women who reported nondaily intake at both time points (HR=0.68, 95% CI 0.48-0.97). Consistent daily tea intake was not associated with decreased melanoma risk. Overall, there is no strong evidence that increasing coffee or tea consumption can lead to a lower melanoma risk. We observed a decrease in melanoma risk among long-term coffee drinkers, but the lack of consistency in the results by dose and type cautioned against overinterpretation of the results.


Penile fracture: penoscrotal approach with degloving of penis after Magnetic Resonance Imaging (MRI).
Fracture of the penis, a relatively uncommon emergency in Urology, consists in the traumatic rupture of the tunica albuginea of the corpus cavernosum. Examination and clinical history can be highly suspicious of penile fracture in the majority of cases and ultrasonography (USS) can be useful to identify the exact location of the tunical rupture, which is proximal in 2/3 of cases and therefore manageable through a penoscrotal approach. Although expensive and not readily available in the acute setting, Magnetic Resonance Imaging (MRI) may play a role in the differential diagnosis with rupture of a circumflex or dorsal vein of the penis or when the tunical rupture is not associated with tear of the overlying Buck's fascia. This form of imaging is more sensitive than USS at identifying the presence of a tunical tear. The treatment of choice is immediate surgical repair, which allows preserving erectile function and minimizing corporeal fibrosis.


Conserved hippocampal cellular pathophysiology but distinct behavioural deficits in a new rat model of FXS.
Recent advances in techniques for manipulating genomes have allowed the generation of transgenic animals other than mice. These new models enable cross-mammalian comparison of neurological disease from core cellular pathophysiology to circuit and behavioural endophenotypes. Moreover they will enable us to directly test whether common cellular dysfunction or behavioural outcomes of a genetic mutation are more conserved across species. Using a new rat model of Fragile X Syndrome, we report that Fmr1 knockout (KO) rats exhibit elevated basal protein synthesis and an increase in mGluR-dependent long-term depression in CA1 of the hippocampus that is independent of new protein synthesis. These defects in plasticity are accompanied by an increase in dendritic spine density selectively in apical dendrites and subtle changes in dendritic spine morphology of CA1 pyramidal neurons. Behaviourally, Fmr1 KO rats show deficits in hippocampal-dependent, but not hippocampal-independent, forms of associative recognition memory indicating that the loss of fragile X mental retardation protein (FMRP) causes defects in episodic-like memory. In contrast to previous reports from mice, Fmr1 KO rats show no deficits in spatial reference memory reversal learning. One-trial spatial learning in a delayed matching to place water maze task was also not affected by the loss of FMRP in rats. This is the first evidence for conservation across mammalian species of cellular and physiological hippocampal phenotypes associated with the loss of FMRP. Furthermore, while key cellular phenotypes are conserved they manifest in distinct behavioural dysfunction. Finally, our data reveal novel information about the selective role of FMRP in hippocampus-dependent associative memory.


Label-free photoacoustic nanoscopy.
Super-resolution microscopy techniques - capable of overcoming the diffraction limit of light - have opened new opportunities to explore subcellular structures and dynamics not resolvable in conventional far-field microscopy. However, relying on staining with exogenous fluorescent markers, these techniques can sometimes introduce undesired artifacts to the image, mainly due to large tagging agent sizes and insufficient or variable labeling densities. By contrast, the use of endogenous pigments allows imaging of the intrinsic structures of biological samples with unaltered molecular constituents. Here, we report label-free photoacoustic (PA) nanoscopy, which is exquisitely sensitive to optical absorption, with an 88 nm resolution. At each scanning position, multiple PA signals are successively excited with increasing laser pulse energy. Because of optical saturation or nonlinear thermal expansion, the PA amplitude depends on the nonlinear incident optical fluence. The high-order dependence, quantified by polynomial fitting, provides super-resolution imaging with optical sectioning. PA nanoscopy is capable of super-resolution imaging of either fluorescent or nonfluorescent molecules.


Secondary production of the fiddler crab Uca rapax from mangrove areas under anthropogenic eutrophication in the Western Atlantic, Brazil.
Fiddler crabs Uca rapax were analyzed in three mangrove areas located in both a lagoon and estuarine system in order to study the influence of eutrophication on their population dynamics and production. Populations at the three sites showed a biased sex ratio. Densities were similar at the three sites, but biomass was higher at the lagoon system. Despite biomass being higher at the most eutrophic site, this site exhibited the lowest production. Regarding age structure, the population inhabiting the less eutrophic site mainly comprised younger crabs. The lower production and smaller P/B ratio found in the more eutrophic site were most likely consequences of a high mortality rate and an aged population. Our study evidences the high plasticity of the fiddler crab U. rapax, and confirms secondary production and P/B ratio estimates as useful tools to assess the effects of environmental change.


An exploratory study to subtype obese binge eaters by personality traits.
Obesity and binge eating disorder (BED) are prevalent conditions that severely affect the quality of life of many people in developed countries, but an effective treatment remains elusive. Personality traits have been studied extensively in this population, leading to different, and at times conflicting, results. Subtyping BED people along these features could add to our knowledge of the disorder. We applied a two-step cluster analysis, followed by bootstrapping validation, to the Temperament and Character Inventory scores of 462 subjects affected by obesity and BED or subthreshold BED. We found two clusters of subjects; however, the categorization in clusters 1 and 2 did not appear to strictly overlap with the distinction between BED and subthreshold BED. The first cluster showed higher harm avoidance and a lower self-directedness. Cluster 1 patients had higher depression, higher eating impulsivity, greater problems with their body image and poorer quality of life than cluster 2 patients. Our results seem to confirm the heterogeneity of the binge eater population and suggest the importance of harm avoidance and self-directedness to subtype these subjects. These results could generate exploratory works regarding personality in obese people with BED to discover more targeted treatments.


Generalized linear mixed models for binary data: are matching results from penalized quasi-likelihood and numerical integration less biased?
Over time, adaptive Gaussian Hermite quadrature (QUAD) has become the preferred method for estimating generalized linear mixed models with binary outcomes. However, penalized quasi-likelihood (PQL) is still used frequently. In this work, we systematically evaluated whether matching results from PQL and QUAD indicate less bias in estimated regression coefficients and variance parameters via simulation. We performed a simulation study in which we varied the size of the data set, probability of the outcome, variance of the random effect, number of clusters and number of subjects per cluster, etc. We estimated bias in the regression coefficients, odds ratios and variance parameters as estimated via PQL and QUAD. We ascertained if similarity of estimated regression coefficients, odds ratios and variance parameters predicted less bias. Overall, we found that the absolute percent bias of the odds ratio estimated via PQL or QUAD increased as the PQL- and QUAD-estimated odds ratios became more discrepant, though results varied markedly depending on the characteristics of the dataset. Given how markedly results varied depending on data set characteristics, specifying a rule above which indicated biased results proved impossible. This work suggests that comparing results from generalized linear mixed models estimated via PQL and QUAD is a worthwhile exercise for regression coefficients and variance components obtained via QUAD, in situations where PQL is known to give reasonable results.


Integrative DNA methylation and gene expression analysis identifies discoidin domain receptor 1 association with idiopathic nonobstructive azoospermia.
To evaluate the association between promoter DNA methylation and discoidin domain receptor 1 (DDR1) gene expression in men with nonobstructive azoospermia (NOA). Comparing fibroblasts cultured from testicular biopsies using a high resolution Infinium 450K methylation array. Basic research laboratory. Men with NOA (n = 16) and with normal spermatogenesis (n = 5). None. Bisulfite clonal sequencing for validation and quantification of CpG methylation of DDR1; gene expression analysis of DDR1 with quantitative polymerase chain reaction and immunohistochemistry to validate the array results at mRNA and protein levels. We validated promoter methylation, mRNA and protein levels of the CpG sites identified from array results. Differentially methylated CpG sites (∼20K) were identified using an F-test in the NOA samples. We identified 20 genes with >30% difference in DNA methylation within the promoter region of men with NOA and fertile controls. Of the aberrantly methylated genes, 10 were hypomethylated and 10 were hypermethylated genes. From the top 10 hypermethylated genes, six genes (MRI1, DCAF12L1, TMEM95, CECR2, DDR1, and NPHS2) were selected for validation because they were shown to be expressed in the testis. Of the six genes expressed in the fibroblasts cultured from testis, DDR1 showed an abnormal gene expression pattern. Three patients (19%) out of the 16 men with NOA for whom gene expression data were available had lower DDR1 expression levels (1.8x fold decrease) than the fertile men, whereas four (25%) men had higher expression levels (2x fold increase) of DDR1 compared with the levels in fertile men. Quantitative analysis by bisulfite clonal sequencing showed that one of the CpG sites (cg13329862) of DDR1 promoter was hypermethylated in NOA patients compared with fertile controls (53% vs. 15%). Immunohistochemical analysis suggests presence of DDR1 within cytoplasm of germ cells and peritubular connective tissue (in men with hypospermatogenesis) and decreased expression of the protein in men with Sertoli-cell only syndrome. Abnormal gene expression of DDR1 is associated with NOA. The functional relevance of aberrant methylation of DDR1 to expression of DDR1 in men with NOA warrants further investigation.


Mapping hot spots of breast cancer mortality in the United States: place matters for Blacks and Hispanics.
The goals of this study were to identify geographic and racial/ethnic variation in breast cancer mortality, and evaluate whether observed geographic differences are explained by county-level characteristics. We analyzed data on breast cancer deaths among women in 3,108 contiguous United States (US) counties from years 2000 through 2015. We applied novel geospatial methods and identified hot spot counties based on breast cancer mortality rates. We assessed differences in county-level characteristics between hot spot and other counties using Wilcoxon rank-sum test and Spearman correlation, and stratified all analysis by race/ethnicity. Among all women, 80 of 3,108 (2.57%) contiguous US counties were deemed hot spots for breast cancer mortality with the majority located in the southern region of the US (72.50%, p value < 0.001). In race/ethnicity-specific analyses, 119 (3.83%) hot spot counties were identified for NH-Black women, with the majority being located in southern states (98.32%, p value < 0.001). Among Hispanic women, there were 83 (2.67%) hot spot counties and the majority was located in the southwest region of the US (southern = 61.45%, western = 33.73%, p value < 0.001). We did not observe definitive geographic patterns in breast cancer mortality for NH-White women. Hot spot counties were more likely to have residents with lower education, lower household income, higher unemployment rates, higher uninsured population, and higher proportion indicating cost as a barrier to medical care. We observed geographic and racial/ethnic disparities in breast cancer mortality: NH-Black and Hispanic breast cancer deaths were more concentrated in southern, lower SES counties.


Use of small bowel imaging for the diagnosis and staging of Crohn's disease--a survey of current UK practice.
This study used a postal survey to assess the current use of small bowel imaging investigations for Crohn's disease within National Health Service (NHS) radiological practice and to gauge gastroenterological referral patterns. Similar questionnaires were posted to departments of radiology (n = 240) and gastroenterology (n = 254) identified, by the databases of the Royal College of Radiologists and British Society of Gastroenterologists. Questionnaires enquired about the use of small bowel imaging in the assessment of Crohn's disease. In particular, questionnaires described clinical scenarios including first diagnosis, disease staging and assessment of suspected extraluminal complications, obstruction and disease flare. The data were stratified according to patient age. 63 (27%) departments of radiology (20 in teaching hospitals and 43 in district general hospitals (DGHs)) and 73 (29%) departments of gastroenterology replied. These departments were in 119 institutions. Of the 63 departments of radiology, 55 (90%) routinely performed barium follow-though (BaFT), 50 (80%) CT, 29 (46%) small bowel ultrasound (SbUS) and 24 (38%) small bowel MRI. BaFT was the most commonly used investigation across all age groups and indications. SbUS was used mostly for patients younger than 40 years of age with low index of clinical suspicion for Crohn's disease (in 44% of radiology departments (28/63)). MRI was most frequently used in patients under 20 years of age for staging new disease (in 27% of radiology departments (17/63)) or in whom obstruction was suspected (in 29% of radiology departments (18/63)). CT was preferred for suspected extraluminal complications or obstruction (in 73% (46/63) and 46% (29/63) of radiology departments, respectively). Gastroenterological referrals largely concurred with the imaging modalities chosen by radiologists, although gastroenterologists were less likely to request SbUS and MRI. BaFT remains the mainstay investigation for luminal small bowel Crohn's disease, with CT dominating for suspected extraluminal complications. There has been only moderate dissemination of the use of MRI and SbUS.


A new functional role of the fibrinogen RGD motif as the molecular switch that selectively triggers integrin alphaIIbbeta3-dependent RhoA activation during cell spreading.
A number of RGD-type integrins rely on a synergistic site in addition to the canonical RGD site for ligand binding and signaling, although it is still unclear whether these two recognition sites function independently, synergistically, or competitively. Experimental evidence has suggested that fibrinogen binding to the RGD-type integrin alphaIIbbeta3 occurs exclusively through the synergistic gamma(400-411) sequence, thus questioning the functional role of the RGD recognition site. Here we have investigated the respective role of the fibrinogen gamma(400-411) sequence and the RGD motif in the molecular events leading to ligand-induced alphaIIbbeta3-dependent Chinese hamster ovary (CHO) cell or platelet spreading, by using intact fibrinogen and well characterized plasmin-generated fibrinogen fragments containing either the RGD motif (fragment C) or the gamma(400-411) sequence (fragment D), and CHO cells expressing resting wild type (alphaIIbbeta3wt), constitutively active (alphaIIbbeta3T562N), or non-functional (alphaIIbbeta3D119Y) receptors. Our data provide evidence that the gamma(400-411) site by itself is able to initiate alphaIIbbeta3 clustering and recruitment of intracellular proteins to early focal complexes, mediating cell attachment, FAK phosphorylation, and Rac1 activation, while the RGD motif subsequently acts as a molecular switch on the beta3 subunit to trigger cell spreading. More importantly, we show that the premier functional role of the RGD site is not to reinforce cell attachment but, rather, to imprint a conformational change on the beta3 subunit leading to maximal RhoA activation and actin cytoskeleton organization in CHO cells as well as in platelets. Finally, alphaIIbbeta3-dependent RhoA stimulation and cell spreading, but not cell attachment, are Src-dependent and phosphoinositide 3-kinase-independent and are inhibited by the Src antagonist PP2.


The impact of parameter identification methods on drug therapy control in an intensive care unit.
This paper investigates the impact of fast parameter identification methods, which do not require any forward simulations, on model-based glucose control, using retrospective data in the Christchurch Hospital Intensive Care Unit. The integral-based identification method has been previously clinically validated and extensively applied in a number of biomedical applications; and is a crucial element in the presented model-based therapeutics approach. Common non-linear regression and gradient descent approaches are too computationally intense and not suitable for the glucose control applications presented. The main focus in this paper is on better characterizing and understanding the importance of the integral in the formulation and the effect it has on model-based drug therapy control. As a comparison, a potentially more natural derivative formulation which has the same computation speed advantages is investigated, and is shown to go unstable with respect to modelling error which is always present clinically. The integral method remains robust.


High level of ciprofloxacin resistance and its molecular background among Campylobacter jejuni strains isolated in the United Arab Emirates.
The antibiotic sensitivity and the serotype and molecular type (MT) distribution of 41 Campylobacter jejuni strains isolated from individual patients in Tawam Hospital, Al Ain, United Arab Emirates, were investigated. While all strains were sensitive to erythromycin (MIC 0.5-4 mg l(-1)), 35 isolates (85.4 %) exhibited resistance to ciprofloxacin (MIC 8-64 mg l(-1)). All resistant strains carried the Thr-86 to Ile mutation in the gyrase A (gyrA) gene, as shown by mismatch amplification mutation assay (MAMA) and confirmed by sequencing. Based on the partial sequences of gyrA, resistant isolates carried 10 distinct alleles, eight of them representing new variants. Strains were assigned to 30 MTs based on the combined results of PFGE and flaA PCR-RFLP typing. Eight of the 35 ciprofloxacin-resistant strains, isolated over a period of more than 1 year, represented the largest MT, also carrying the same allelic variant of the gyrA gene. These results show that the local incidence of fluoroquinolone resistance among C. jejuni is one of the highest reported worldwide. It was also demonstrated that stable MTs could persist for a relatively long time among the clonally unrelated antibiotic-resistant isolates of C. jejuni. The data also emphasize the need to replace fluoroquinolones as empirical therapy for diarrhoea of undiagnosed aetiology.


Exploiting Transient Protein States for the Design of Small-Molecule Stabilizers of Mutant p53.
The destabilizing p53 cancer mutation Y220C creates an extended crevice on the surface of the protein that can be targeted by small-molecule stabilizers. Here, we identify different classes of small molecules that bind to this crevice and determine their binding modes by X-ray crystallography. These structures reveal two major conformational states of the pocket and a cryptic, transiently open hydrophobic subpocket that is modulated by Cys220. In one instance, specifically targeting this transient protein state by a pyrrole moiety resulted in a 40-fold increase in binding affinity. Molecular dynamics simulations showed that both open and closed states of this subsite were populated at comparable frequencies along the trajectories. Our data extend the framework for the design of high-affinity Y220C mutant binders for use in personalized anticancer therapy and, more generally, highlight the importance of implementing protein dynamics and hydration patterns in the drug-discovery process.


A combined approach exploring gene function based on worm-human orthology.
Many aspects of the nematode Caenorhabditis elegans biology are conserved between invertebrates and vertebrates establishing this particular organism as an excellent genetic model. Because of its small size, large populations and self-fertilization of the hermaphrodite, functional predictions carried out by genetic modifications as well as RNAi screens, can be rapidly tested. In order to explore the function of a set of C. elegans genes of unknown function, as well as their potential functional roles in the human genome, we performed a phylogenetic analysis to select the most probable worm orthologs. A total of 13 C. elegans genes were subjected to down-regulation via RNAi and characterization of expression profiles using GFP strains. Previously unknown distinct expression patterns were observed for four of the analyzed genes, as well as four visible RNAi phenotypes. In addition, subcellular protein over-expression profiles of the human orthologs for seven out of the thirteen genes using human cells were also analyzed. By combining a whole-organism approach using C. elegans with complementary experimental work done on human cell lines, this analysis extends currently available information on the selected set of genes.


Atmospheric pressure mass spectrometric imaging of bio-tissue specimen using electrospray-assisted CW laser desorption and ionization source.
When a tissue slice pretreated with gold nanoparticles is irradiated with a focused 532-nm continuous wave laser, desorption is observed to be uniform and stable, and its shape is sharp and steep. However, since the desorbed molecules are still electrically neutral particles in atmospheric pressure (AP), additional procedure of ionizing them is necessary for AP mass spectrometry (AP-MS) analysis. Therefore, the authors have combined an electrospray device with a simple chamber connected to the airflow-assisted particle transport equipment mounted at the mass spectrometer inlet. Subsequent ionization processes using an electrospray device enable the detection of several types of diacylglycerol molecules above 500 Da, which cannot be detected with the use of AP plasma jets. The authors also developed a remote AP-MS using a long and flexible sampling probe and a fiber laser with a slight modification of the proposed AP desorption and ionization method.


Bleeding peptic ulcer: characteristics and outcomes in Newcastle, NSW.
Peptic ulcer disease risk factors have changed, as has the impact of treatment on morbidity and mortality. Recent data on clinical presentation and outcome are sparse in Australia. To determine the characteristics and outcome of patients presenting with a bleeding peptic ulcer to a tertiary referral centre. We evaluated patients diagnosed with peptic ulcer bleeding between 2004 and 2008 at a tertiary referral hospital. Variables assessed included demographic data, comorbidities, medication use and Rockall score. Outcomes of interest were the time to endoscopy, peptic ulcer treatment, transfusion requirements, urgent surgery and survival. Peptic ulcers were confirmed in 265 patients (55% male), of which 145 were gastric and 119 duodenal. The mean age was 71 years. On admission 38% of patients had haemodynamic instability and 92% had one or more comorbidity. Consumption of ulcerogenic medications at the time of admission was frequent (non-steroidal anti-inflammatory drugs (NSAIDs) 22%, aspirin 41%, clopidogrel or warfarin 10%) and proton pump inhibitors infrequent (15%). A gastroenterologist managed all patients according to their usual practice. Only a minority of patients received over three units of packed red cells. Few patients were referred for surgery (3%) or died (3%), but both events were significantly higher for the duodenal ulcer group. The characteristics and outcomes in patients with peptic ulcer bleeding have changed. Peptic ulcer disease remains a public health problem with modifiable risk factors, such as Helicobacter pylori infection and NSAIDs, which should be targeted to reduce the burden of illness.


Exacerbation of demyelinating syndrome after exposure to wireless modem with public hotspot.
In August 2003, 48-year-old JS of Colorado, USA, a fitness therapist and sports nutritionist, contracted neuroinvasive West Nile virus which left her with disabilities due to spinal axonal damage.In August 2014, she suddenly developed symptoms very much like her acute West Nile infection 11 years ago, including focal seizures, ataxia, vertigo and headaches. Her blood count looked normal so there was no obvious infection. What struck her as odd was that when she left her apartment for any length of time, the symptoms stopped. She found out that a new type of wireless modem, enabled for both personal use and functioning as a public hotspot designed to reach up to 100 m, had been installed in the flat under hers.Her neighbor replaced the modem with a router without the hotspot feature. After that, the seizures stopped immediately, and the other symptoms faded gradually, after which she was fine and again could sleep well. Later, when another activated hotspot was installed in an adjacent flat, JS once again noticed symptoms.A possible association between electrohypersensitivity, myelin integrity and exposure to low-intensity radiofrequency electromagnetic fields (RF-EMF) typical in the modern world has recently been proposed. Since the West Nile virus attacks both the nerve cells and the glial ones, one explanation to the above observed case effects is that the initial virus attack and the wireless modem's RF-EMF affect the nervous system through the very same, or similar, avenues, and maybe both via the oligodendrocytes.


Electrifying discourse: Anodal tDCS of the primary motor cortex selectively reduces action appraisal in naturalistic narratives.
Non-invasive stimulation of the primary motor cortex (M1) modulates processing of decontextualized action words and sentences (i.e., verbal units denoting bodily motion). This suggests that language comprehension hinges on brain circuits mediating the bodily experiences evoked by verbal material. Yet, despite its relevance to constrain mechanistic language models, such a finding fails to reveal whether and how relevant circuits operate in the face of full-blown, everyday texts. Using a novel naturalistic discourse paradigm, we examined whether direct modulation of M1 excitability influences the grasping of narrated actions. Following random group assignment, participants received anodal transcranial direct current stimulation over the left M1, or sham stimulation of the same area, or anodal stimulation of the left ventrolateral prefrontal cortex. Immediately afterwards, they listened to action-laden and neutral stories and answered questions on information realized by verbs (denoting action and non-action processes) and circumstances (conveying locative or temporal details). Anodal stimulation of the left M1 selectively decreased outcomes on action-relative to non-action information -a pattern that discriminated between stimulated and sham participants with 74% accuracy. This result was particular to M1 and held irrespective of the subjects' working memory and vocabulary skills, further attesting to its specificity. Our findings suggest that offline modulation of motor-network excitability might lead to transient unavailability of putative resources needed to evoke actions in naturalistic texts, opening promising avenues for the language embodiment framework.


Spinal facet joint biomechanics and mechanotransduction in normal, injury and degenerative conditions.
The facet joint is a crucial anatomic region of the spine owing to its biomechanical role in facilitating articulation of the vertebrae of the spinal column. It is a diarthrodial joint with opposing articular cartilage surfaces that provide a low friction environment and a ligamentous capsule that encloses the joint space. Together with the disc, the bilateral facet joints transfer loads and guide and constrain motions in the spine due to their geometry and mechanical function. Although a great deal of research has focused on defining the biomechanics of the spine and the form and function of the disc, the facet joint has only recently become the focus of experimental, computational and clinical studies. This mechanical behavior ensures the normal health and function of the spine during physiologic loading but can also lead to its dysfunction when the tissues of the facet joint are altered either by injury, degeneration or as a result of surgical modification of the spine. The anatomical, biomechanical and physiological characteristics of the facet joints in the cervical and lumbar spines have become the focus of increased attention recently with the advent of surgical procedures of the spine, such as disc repair and replacement, which may impact facet responses. Accordingly, this review summarizes the relevant anatomy and biomechanics of the facet joint and the individual tissues that comprise it. In order to better understand the physiological implications of tissue loading in all conditions, a review of mechanotransduction pathways in the cartilage, ligament and bone is also presented ranging from the tissue-level scale to cellular modifications. With this context, experimental studies are summarized as they relate to the most common modifications that alter the biomechanics and health of the spine-injury and degeneration. In addition, many computational and finite element models have been developed that enable more-detailed and specific investigations of the facet joint and its tissues than are provided by experimental approaches and also that expand their utility for the field of biomechanics. These are also reviewed to provide a more complete summary of the current knowledge of facet joint mechanics. Overall, the goal of this review is to present a comprehensive review of the breadth and depth of knowledge regarding the mechanical and adaptive responses of the facet joint and its tissues across a variety of relevant size scales.


Science classroom inquiry (SCI) simulations: a novel method to scaffold science learning.
Science education is progressively more focused on employing inquiry-based learning methods in the classroom and increasing scientific literacy among students. However, due to time and resource constraints, many classroom science activities and laboratory experiments focus on simple inquiry, with a step-by-step approach to reach predetermined outcomes. The science classroom inquiry (SCI) simulations were designed to give students real life, authentic science experiences within the confines of a typical classroom. The SCI simulations allow students to engage with a science problem in a meaningful, inquiry-based manner. Three discrete SCI simulations were created as website applications for use with middle school and high school students. For each simulation, students were tasked with solving a scientific problem through investigation and hypothesis testing. After completion of the simulation, 67% of students reported a change in how they perceived authentic science practices, specifically related to the complex and dynamic nature of scientific research and how scientists approach problems. Moreover, 80% of the students who did not report a change in how they viewed the practice of science indicated that the simulation confirmed or strengthened their prior understanding. Additionally, we found a statistically significant positive correlation between students' self-reported changes in understanding of authentic science practices and the degree to which each simulation benefitted learning. Since SCI simulations were effective in promoting both student learning and student understanding of authentic science practices with both middle and high school students, we propose that SCI simulations are a valuable and versatile technology that can be used to educate and inspire a wide range of science students on the real-world complexities inherent in scientific study.


Plasmodium vivax infections in U.S. Army troops: failure of primaquine to prevent relapse in studies from Somalia.
Different strains of Plasmodium vivax vary in their sensitivity to primaquine, the only drug that prevents relapses. Described are the clinical data and relapse pattern for 75 soldiers treated for vivax malaria since returning from Somalia. Following their initial attack of malaria, 60 of the 75 cases received a standard course of primaquine (15 mg base daily for 14 days). Twenty-six of the 60 soldiers subsequently relapsed for a failure rate of 43%. Eight soldiers had a second relapse following primaquine therapy after both the primary attack and first relapse. Three of these soldiers had received a higher dosage of primaquine (30 mg base daily for 14 days) after their second attack. The apparent ineffectiveness of primaquine therapy in preventing relapses suggests the presence of primaquine-resistant P. vivax strains in Somalia.


Development, validation and evaluation of an analytical method for the determination of monomeric and oligomeric procyanidins in apple extracts.
There is a lack of data for individual oligomeric procyanidins in apples and apple extracts. Our aim was to develop, validate and evaluate an analytical method for the separation, identification and quantification of monomeric and oligomeric flavanols in apple extracts. To achieve this, we prepared two types of flavanol extracts from freeze-dried apples; one was an epicatechin-rich extract containing ∼30% (w/w) monomeric (-)-epicatechin which also contained oligomeric procyanidins (Extract A), the second was an oligomeric procyanidin-rich extract depleted of epicatechin (Extract B). The parameters considered for method optimisation were HPLC columns and conditions, sample heating, mass of extract and dilution volumes. The performance characteristics considered for method validation included standard linearity, method sensitivity, precision and trueness. Eight laboratories participated in the method evaluation. Chromatographic separation of the analytes was best achieved utilizing a Hilic column with a binary mobile phase consisting of acidic acetonitrile and acidic aqueous methanol. The final method showed linearity for epicatechin in the range 5-100μg/mL with a correlation co-efficient >0.999. Intra-day and inter-day precision of the analytes ranged from 2 to 6% and 2 to 13% respectively. Up to dp3, trueness of the method was >95% but decreased with increasing dp. Within laboratory precision showed RSD values <5 and 10% for monomers and oligomers, respectively. Between laboratory precision was 4 and 15% (Extract A) and 7 and 30% (Extract B) for monomers and oligomers, respectively. An analytical method for the separation, identification and quantification of procyanidins in an apple extract was developed, validated and assessed. The results of the inter-laboratory evaluation indicate that the method is reliable and reproducible.


Apathy, but not depression, predicts all-cause dementia in cerebral small vessel disease.
To determine whether apathy or depression predicts all-cause dementia in small vessel disease (SVD) patients. Analyses used two prospective cohort studies of SVD: St. George's Cognition and Neuroimaging in Stroke (SCANS; n=121) and Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort (RUN DMC; n=352). Multivariate Cox regressions were used to predict dementia using baseline apathy and depression scores in both datasets. Change in apathy and depression was used to predict dementia in a subset of 104 participants with longitudinal data from SCANS. All models were controlled for age, education and cognitive function. Baseline apathy scores predicted dementia in SCANS (HR 1.49, 95% CI 1.05 to 2.11, p=0.024) and RUN DMC (HR 1.05, 95% CI 1.01 to 1.09, p=0.007). Increasing apathy was associated with dementia in SCANS (HR 1.53, 95% CI 1.08 to 2.17, p=0.017). In contrast, baseline depression and change in depression did not predict dementia in either dataset. Including apathy in predictive models of dementia improved model fit. Apathy, but not depression, may be a prodromal symptom of dementia in SVD, and may be useful in identifying at-risk individuals.


Y1-receptors regulate the expression of Y2-receptors in distinct mouse forebrain areas.
Y-receptor-knockout mice have become an important tool to elucidate specific physiological roles of individual Y-receptors. However, their phenotypes are not always confirmatory to results obtained by pharmacological investigations in vivo or in vitro. These discrepancies may, at least in part, be due to compensatory changes in the expression of remaining Y-receptor types. To determine whether deletion of individual Y-receptors results in altered mRNA expression and/or binding toward other Y-receptor types, we applied in-situ hybridization and radioligand-binding studies on brain slices of Npy1r-, Npy2r- or Npy5r-knockout mice. Significant changes were seen in Y1-receptor-deficient mice. Thus, Y2-receptor mRNA and (125)I-peptide YY(3-36) binding in the hippocampus proper were increased by up to 55% and 89%, respectively. Similar increases in (125)I-peptide YY(3-36) binding were observed in the caudo-dorsal extension of the lateral septum, an area heavily targeted by hippocampal projections and involved in Y1-receptor-regulated anxiety. Increased (125)I-peptide YY(3-36) binding and Y2-receptor mRNA levels were also observed in the medial amygdaloid nucleus. In contrast, (125)I-peptide YY(3-36) binding was reduced in the central amygdaloid nucleus. Y2-receptor mRNA in the intermediate part of the lateral septum was reduced by 42%. Only minimal changes were observed in Y2- or Y5-receptor-deficient mice. Our results demonstrate that compensatory changes in the expression of Y2-receptors occur in Y1-receptor-deficient mice. These adaptations are likely to contribute to changed physiological function. Thus, alterations in Y2-receptors have to be taken in account upon discussion of Y1-receptor function, especially in emotional aspects like anxiety and aggression, but also alcoholism.


Aqueous humor pilocarpine and timolol levels after instillation of the single drug or in combination.
Aqueous humor levels of pilocarpine and timolol in rabbits after administration of either 2% pilocarpine or 0.5% timolol in single-drug solutions were compared with the concentrations found after instillation of a fixed combination of 0.5% timolol and 2% pilocarpine drops. Time intervals considered were 15 min, 30 min, 1 hr, 4 hr, and 8 hr after application. Drug concentrations were analyzed in individual aqueous samples by high-performance liquid chromatography. No statistically significant differences in either pilocarpine or timolol concentrations in aqueous humor were found at any time tested between the single-drug preparations and the combination.


Effects of carbonated liquids on oropharyngeal swallowing measures in people with neurogenic dysphagia.
Aspiration is common in adults with neurogenic dysphagia and pharyngeal delay. This can lead to dehydration, malnutrition, and aspiration pneumonia. Diet modifications aimed at reducing thin liquid aspiration are partially successful or unpalatable or both. Carbonated liquids show some potential in influencing swallowing behavior. However, there is a paucity of evidence to support this intervention. This study compares the effects of carbonated thin liquids (CTL) with that of noncarbonated thin liquids (NCTL) on oropharyngeal swallowing in adults with neurogenic dysphagia and examines the palatability of the CTL stimulus. Seventeen people with pharyngeal delay attended for videofluoroscopy (VFSS). Outcome measures were oral transit time (OTT), pharyngeal transit time (PTT), stage transition duration (STD), initiation of the pharyngeal swallow (IPS), penetration-aspiration scale (PENASP), and pharyngeal retention (PR). A modification of Quartermaster Hedonic Scale (AQHS) was employed to assess palatability of the CTL. CTL vs. NCTL significantly decreased penetration and aspiration on 5-ml (P = 0.028) and 10-ml (P = 0.037) swallows. CTL had no significant effect on OTT, PTT, IPS, and PR for any volume of bolus. Only one participant disliked the CTL stimulus. These findings support the hypothesis that oropharyngeal swallowing can be modulated in response to sensory stimuli. Implications for research and clinical practice are discussed.


Attitudes and Perceptions of Medical Undergraduates Towards Mobile Learning (M-learning).
Mobile technology is one of the latest extensions of technological innovations that can be integrated into medical education. With the aid of these devices, students learn faster outside the classroom by having quick access to the internet and easy retrieval of required health related learning resources to keep alongside of recent trend and development. In medicine practice one has to continuously update his/her medical knowledge and mobile learning will serve as a tool for self-directed learning. To explore the attitudes and perceptions of undergraduate students towards M-learning. This educational research included 90 third year MBBS students having clinical posting under the Department of Community Medicine from tertiary healthcare institute in Nashik. Students learning approach was studied with the help of pre-validated questionnaire to know whether they have deep or surface approach to learning. M-learning group was formed on mobile social app to supplement conventional teaching-learning. One subject topic (Tuberculosis, Dengue fever/DHF, Hypertension and Diabetes Mellitus etc.) per week was allotted and after conventional teaching on first day of week the learning materials for the topic chosen for that week were uploaded on the group and students could download as well as share their ideas, learning resources, ask doubts and answer questions at least twice weekly through this mobile platform anytime, anywhere. At the end of three months students attitudes and perceptions towards M-learning were studied by pre-validated structured questionnaires. A five point Likert scale was used (5= strongly agree to 1= strongly disagree) for answering each item of all three questionnaires. The score of 60% (90 out of 150) and the score of 75% (30 out of 40) for each item was considered as the measure that indicates whether or not the student had a positive attitude and perceived the importance of M-learning respectively. Utilisation of M-learning was also studied. It was found that 47 (52.2%) students had deep learning approach, 10 (11.1%) students had surface learning approach. An 80% of students had positive attitude towards M-learning and 76.7% students had perceived the importance of M-learning. A 52.2% of students were actively involved in M-learning group for learning purpose. But 57.8% students did not download (at least twice weekly) the shared reference material, 38.9% students never read and/or replied to the questions asked and 60.0% students never asked any doubts/questions related to the discussion. Students had positive attitude and perceived the importance of M-learning. But when they were provided with the opportunity, they did not show appreciable M-learning utilization. This could be because, M-learning was not implemented by all departments; also it was not the part of student's regular assessment and probably a lesser study duration.


Evaluation of the dark-medium objective lens in counting asbestos fibers by phase-contrast microscopy.
A Japanese round-robin study revealed that analysts who used a dark-medium (DM) objective lens reported higher fiber counts from American Industrial Hygiene Association (AIHA) Proficiency Analytical Testing (PAT) chrysotile samples than those using a standard objective lens, but the cause of this difference was not investigated at that time. The purpose of this study is to determine any major source of this difference by performing two sets of round-robin studies. For the first round-robin study, 15 AIHA PAT samples (five each of chrysotile and amosite generated by water-suspended method, and five chrysotile generated by aerosolization method) were prepared with relocatable cover slips and examined by nine laboratories. A second round-robin study was then performed with six chrysotile field sample slides by six out of nine laboratories who participated in the first round-robin study. In addition, two phase-shift test slides to check analysts' visibility and an eight-form diatom test plate to compare resolution between the two objectives were examined. For the AIHA PAT chrysotile reference slides, use of the DM objective resulted in consistently higher fiber counts (1.45 times for all data) than the standard objective (P-value < 0.05), regardless of the filter generation (water-suspension or aerosol) method. For the AIHA PAT amosite reference and chrysotile field sample slides, the fiber counts between the two objectives were not significantly different. No statistically significant differences were observed in the visibility of blocks of the test slides between the two objectives. Also, the DM and standard objectives showed no pattern of differences in viewing the fine lines and/or dots of each species images on the eight-form diatom test plate. Among various potential factors that might affect the analysts' performance of fiber counts, this study supports the greater contrast caused by the different phase plate absorptions as the main cause of high counts for the AIHA PAT chrysotile slides using the DM objective. The comparison of fiber count ratios (DM/standard) between the AIHA PAT chrysotile samples and chrysotile field samples indicates that there is a fraction of fibers in the PAT samples approaching the theoretical limit of visibility of the phase-contrast microscope with 3-degree phase-shift. These fibers become more clearly visible through the greater contrast from the phase plate absorption of the DM objective. However, as such fibers are not present in field samples, no difference in counts between the two objectives was observed in this study. The DM objective, therefore, could be allowed for routine fiber counting as it will maintain continuity with risk assessments based on earlier phase-contrast microscopy fiber counts from field samples. Published standard methods would need to be modified to allow a higher aperture specification for the objective.


Correlations between physicochemical properties of PAHs and their distribution in soil, moss and reindeer dung at Ny-Alesund of the Arctic.
Concentrations of 16 polycyclic aromatic hydrocarbons (PAHs) in soil, moss and reindeer dung collected at Ny-Alesund of the Arctic were measured to investigate their accumulation trends and distribution in the three compartments. Compared with the other regions, the proportions of 2 + 3 ring PAHs to the total PAHs were higher, whereas the proportions of 5 + 6 ring PAHs were lower in the three compartments at Ny-Alesund. Significant log/log-linear relationship was observed between the sub-cooled liquid vapor pressure (p(L)( degrees )) and the soil/moss quotient (Q(SM)). The relation was similar to the relationship between the gas/particle partition coefficient (K(P)) and p(L)( degrees ) of PAHs, implying Q(SM) would be a "mirror image" of K(P). Excellent log/log-linear relationships were observed between Q(SM) and K(OA) as well as between the moss/dung quotient (Q(MD)) and K(OW). The results presented here indicate the physicochemical properties are suitable for characterizing the distribution of PAHs in soil, moss and reindeer dung.


Tackling reporting issues and variation in behavioural weight management interventions: Design and piloting of the standardized reporting of adult behavioural weight management interventions to aid evaluation (STAR-LITE) template.
In the United Kingdom, the National Institute for Health and Care Excellence make recommendations to guide the local-level selection and implementation of adult behavioural weight management interventions (BWMIs) which lack specificity. The reporting of BWMIs is generally poorly detailed, resulting in difficulties when comparing effectiveness, quality and appropriateness for participants. This non-standardized reporting makes meta-analysis of intervention data impossible, resulting in vague guidance based on weak evidence, reinforcing the urgent need for consistency and detail within BWMI description. STAR-LITE - a 4-section, 119-item standardized adult BWMI reporting template - was developed and tested using a two-phase process. After initial design, the template was piloted using adult behavioural weight management RCTs and currently implemented UK BWMI mapping information to further refine the template and examine current reporting and variance. Overall, reporting quality of weight management RCTs was poor, and large variance across different components of real-world BWMIs was observed. Non-specific guidance and wide variation in adult BWMIs are likely linked to inadequate RCT reporting quality and the inability to perform reliable comparisons of data. Future use of STAR-LITE would facilitate the consistent, detailed reporting of adult BWMIs, supporting their evaluation and comparison, to ultimately inform effective policy and improve weight management practice.


Case fatality rates based on population estimates of influenza-like illness due to novel H1N1 influenza: New York City, May-June 2009.
The public health response to pandemic influenza is contingent on the pandemic strain's severity. In late April 2009, a potentially pandemic novel H1N1 influenza strain (nH1N1) was recognized. New York City (NYC) experienced an intensive initial outbreak that peaked in late May, providing the need and opportunity to rapidly quantify the severity of nH1N1. Telephone surveys using rapid polling methods of approximately 1,000 households each were conducted May 20-27 and June 15-19, 2009. Respondents were asked about the occurrence of influenza-like illness (ILI, fever with either cough or sore throat) for each household member from May 1-27 (survey 1) or the preceding 30 days (survey 2). For the overlap period, prevalence data were combined by weighting the survey-specific contribution based on a Serfling model using data from the NYC syndromic surveillance system. Total and age-specific prevalence of ILI attributed to nH1N1 were estimated using two approaches to adjust for background ILI: discounting by ILI prevalence in less affected NYC boroughs and by ILI measured in syndromic surveillance data from 2004-2008. Deaths, hospitalizations and intensive care unit (ICU) admissions were determined from enhanced surveillance including nH1N1-specific testing. Combined ILI prevalence for the 50-day period was 15.8% (95% CI:13.2%-19.0%). The two methods of adjustment yielded point estimates of nH1N1-associated ILI of 7.8% and 12.2%. Overall case-fatality (CFR) estimates ranged from 0.054-0.086 per 1000 persons with nH1N1-associated ILI and were highest for persons>or=65 years (0.094-0.147 per 1000) and lowest for those 0-17 (0.008-0.012). Hospitalization rates ranged from 0.84-1.34 and ICU admission rates from 0.21-0.34 per 1000, with little variation in either by age-group. ILI prevalence can be quickly estimated using rapid telephone surveys, using syndromic surveillance data to determine expected "background" ILI proportion. Risk of severe illness due to nH1N1 was similar to seasonal influenza, enabling NYC to emphasize preventing severe morbidity rather than employing aggressive community mitigation measures.


Short term elevation in dietary protein intake does not worsen insulin resistance or lipids in older adults with metabolic syndrome: a randomized-controlled trial.
There is a great deal of controversy as to whether higher protein intake improves or worsens insulin sensitivity in humans. The purpose of the study was to determine the influence of a short-term elevation in dietary protein on hepatic and peripheral insulin sensitivity in twelve older subjects (51-70 yrs) with metabolic syndrome. Individuals were randomly assigned to one of the dietary groups: recommended protein intake (RPI, 10% of daily calorie intake) or elevated protein intake (EPI, 20% of daily calorie intake) for 4 weeks. Prior to and immediately following the dietary intervention, subjects were studied with primed continuous infusion of [6,6-2H2]glucose and [1-3C]glucose dissolved in drink during the dual tracer oral glucose tolerance test (DT OGTT) to determine hepatic and peripheral insulin sensitivity. Plasma lipids were measured pre- and post-dietary intervention. In both intervention groups: 1) hepatic insulin sensitivity as assessed by the endogenous glucose rate of appearance (glucose Ra), 2) peripheral insulin sensitivity as assessed by the metabolic clearance rate of glucose normalized to plasma glucose concentration (MCR) and/or the rate of glucose utilization (Rd) or 3) glucose/insulin AUC were unaffected by the diets. Moreover, fasting lipid was not affected by RPI or EPI. Our findings suggest that a short-term elevation in EPI with correspondingly higher branched chain amino acid (BCAA) contents has no detrimental impact on hepatic and peripheral insulin sensitivity or plasma lipid parameters in older adults with metabolic syndrome. ClinicalTrials.gov Identifier: NCT02885935; This trial was registered retrospectively (Study start date, April 01, 2013, date of registration, August 26, 2016).


Enteral stents.
The American Society for Gastrointestinal Endoscopy (ASGE) Technology Committee provides reviews of existing, new, or emerging endoscopic technologies that have an impact on the practice of GI endoscopy. Evidence-based methodology is used, with a MEDLINE literature search to identify pertinent clinical studies on the topic and a MAUDE (U.S. Food and Drug Administration Center for Devices and Radiological Health) database search to identify the reported complications of a given technology. Both are supplemented by accessing the "related articles" feature of PubMed and by scrutinizing pertinent references cited by the identified studies. Controlled clinical trials are emphasized, but in many cases, data from randomized, controlled trials are lacking. In such cases, large case series, preliminary clinical studies, and expert opinions are used. Technical data are gathered from traditional and Web-based publications, proprietary publications, and informal communications with pertinent vendors. Technology Status Evaluation Reports are drafted by 1 or 2 members of the ASGE Technology Committee, reviewed and edited by the committee as a whole, and approved by the Governing Board of the ASGE. When financial guidance is indicated, the most recent coding data and list prices at the time of publication are provided. For this review, the MEDLINE database was searched through August 2010 for articles related to enteral, esophageal, duodenal, and colonic stents. Technology Status Evaluation Reports are scientific reviews provided solely for educational and informational purposes. Technology Status Evaluation Reports are not rules and should not be construed as establishing a legal standard of care or as encouraging, advocating, requiring, or discouraging any particular treatment or payment for such treatment.


Prevalence of Hepatitis C virus and its risk factors in blood donors in district Peshawar.
The current study was designed in order to elucidate the most sensitive method for daily practice as well as to evaluate the risk factors for HCV infection associated with blood transfusion in District Peshawar. A total of 1400 healthy volunteer blood donors were tested for Anti-HCV. A questionnaire was used to evaluate the risk factors. Initial testing of all blood samples was done by Immuno Chromatographic Technique (ICT) and confirmed by micro particle enzyme immunoassay (MEIA) and Enzyme Linked Immunosorbent Assay (ELISA). The comparison among ICT, ELISA and MEIA techniques was also evaluated for the purpose of sensitivity. Among 1400 blood donors, 26 (1.85%) cases were found positive for Anti-HCV. These 26 cases were positive on MEIA, 16 individuals were positive on ELISA while 14 were positive on ICT. These 26 cases had different histories of dental treatment (50%), traveled abroad (23.07%), surgery (11.53%), blood transfusion (7.69%) and unknown reason (7.69%). Among all these different histories of dental treatment and blood transfusion were the main risk factors for HCV infection. The results revealed that MEIA is a quick and reliable technique for routine screening of blood donors particularly for controlling the spread of HCV.


Long-term surgical and hardware-related complications of deep brain stimulation.
To evaluate the incidence of surgical and hardware-associated complications of deep brain stimulation (DBS) for a range of movement disorders. The study design is a retrospective analysis and review of surgical and hardware complications of DBS performed by a single surgeon from 1999 to 2009. A total of 153 cases of DBS (298 electrodes) for various movement disorders and a minimum follow-up of 1 year have been included. Two patients could not be implanted. A further 54 patients who underwent change of the implantable pulse generator (IPG) have been included for analysis of hardware-related complications. The mean follow-up was 64 ± 36.15 (range = 12-129) months for the DBS group. Twenty-four (15.6%) patients developed complications. Confusion occurred in 3.9%, vasovagal attack in 1.9%, lead migration/misplaced lead in 2.5%, erosion and infection in 4.5% and IPG malfunction occurred in 1.4% of the patients. When calculated with respect to the number of electrodes and IPG replacements, the complication rate was lower (11.9%). Three patients had their system explanted, two of them being patients with dystonia who had inadvertently damaged their operative site. DBS surgery is a relatively safe surgery, with most of the complications being minor, without long-term morbidity. The complication rate in elderly (age ≥65 years) is comparable to that in younger patients. However, confusion is more frequent in this age group, and patients and relatives can be prepared to accept this as a transient morbidity.


Enhanced performance of Cr,Yb:YAG microchip laser by bonding Yb:YAG crystal.
Highly efficient, laser-diode pumped Yb:YAG/Cr,Yb:YAG self-Q-switched microchip lasers by bonding Yb:YAG crystal have been demonstrated for the first time to our best knowledge. The effect of transmission of output coupler (T(oc)) on the enhanced performance of Yb:YAG/Cr,Yb:YAG microchip lasers has been investigated and found that the best laser performance was achieved with T(oc) = 50%. Slope efficiency of over 38% was achieved. Average output power of 0.8 W was obtained at absorbed pump power of 2.5 W; corresponding optical-to-optical efficiency of 32% was obtained. Laser pulses with pulse width of 1.68 ns, pulse energy of 12.4 μJ, and peak power of 7.4 kW were obtained. The lasers oscillated in multi-longitudinal modes. The wide separation of longitudinal modes was attributed to the mode selection by combined etalon effect of Cr,Yb:YAG, Yb:YAG thin plates and output coupler. Stable periodical pulse trains at different pump power levels have been observed owing to the longitudinal modes coupling and competition.


Incidental memory of younger and older adults for objects encountered in a real world context.
Effects of context on the perception of, and incidental memory for, real-world objects have predominantly been investigated in younger individuals, under conditions involving a single static viewpoint. We examined the effects of prior object context and object familiarity on both older and younger adults' incidental memory for real objects encountered while they traversed a conference room. Recognition memory for context-typical and context-atypical objects was compared with a third group of unfamiliar objects that were not readily named and that had no strongly associated context. Both older and younger adults demonstrated a typicality effect, showing significantly lower 2-alternative-forced-choice recognition of context-typical than context-atypical objects; for these objects, the recognition of older adults either significantly exceeded, or numerically surpassed, that of younger adults. Testing-awareness elevated recognition but did not interact with age or with object type. Older adults showed significantly higher recognition for context-atypical objects than for unfamiliar objects that had no prior strongly associated context. The observation of a typicality effect in both age groups is consistent with preserved semantic schemata processing in aging. The incidental recognition advantage of older over younger adults for the context-typical and context-atypical objects may reflect aging-related differences in goal-related processing, with older adults under comparatively more novel circumstances being more likely to direct their attention to the external environment, or age-related differences in top-down effortful distraction regulation, with older individuals' attention more readily captured by salient objects in the environment. Older adults' reduced recognition of unfamiliar objects compared to context-atypical objects may reflect possible age differences in contextually driven expectancy violations. The latter finding underscores the theoretical and methodological value of including a third type of objects--that are comparatively neutral with respect to their contextual associations--to help differentiate between contextual integration effects (for schema-consistent objects) and expectancy violations (for schema-inconsistent objects).


Barrett's metaplasia.
The rate of oesophageal adenocarcinoma is increasing in the western world and has a poor prognosis mainly because individuals present at a late stage. Attempts to intervene at an early stage of tumour progression have not proven cost effective, although lesions identified during surveillance programmes have a better prognosis. As a consequence, there has been renewed interest in strategies that might prevent the precursor lesion Barrett's oesophagus. Furthermore, there is an improved understanding of genetic and environmental interactions necessary for the clonal expansion and propagation of metaplastic premalignant lesions. Clearly, three mechanisms promote cancer progression--inheritance of germ-line mutations or polymorphisms, sporadic mutagenesis, and local epigenetic alterations. Locally produced cytokines and bile acids in the refluxate create a microenvironment that sets the scene for metaplastic transformation of the oesophageal epithelium, mainly by directly affecting metaplastic stem cells.


Relationships among display features, eye movement characteristics, and reaction time in visual search.
The relative contribution of number of fixations and fixation duration to reaction time in visual search was investigated. Ten participants (age 20-24 years) took part in each of two experiments. In Experiment 1, the experimental factors were display type (icon and file name), organization (arrangements with and without grouping), and number of stimuli presented (4, 8, and 16). In Experiment 2, a search task for a target stimulus (three prespecified random letters) was conducted, and the experimental factor was the display's layout complexity. Multiple regression analysis was used to examine whether reaction time was explained by a mediational model in which reaction time is mediated by eye movements and display features are not directly related to reaction time. The mediational model was not supported, and the effects of display features on reaction time were not attributable solely to eye movements. The interaction between number of fixations and fixation duration was also explored as a function of display features. As the display feature changed and the task became more difficult, the contribution of the number of fixations to explain the variation in reaction time became dominant for both experiments. Potential applications include measurements of cognitive ability, eye muscle balance disorders, and binocular fusion ability.


Autophagy-Modulated Human Bone Marrow-Derived Mesenchymal Stem Cells Accelerate Liver Restoration in Mouse Models of Acute Liver Failure.
Mesenchymal stem cells (MSCs) have been recently received increasing attention for cell-based therapy, especially in regenerative medicine. However, the low survival rate of these cells restricts their therapeutic applications. It is hypothesized that autophagy might play an important role in cellular homeostasis and survival. This study aims to investigate the regenerative potentials of autophagy-modulated MSCs for the treatment of acute liver failure (ALF) in mice. ALF was induced in mice by intraperitoneal injection of 1.5 ml/kg carbon tetrachloride. Mice were intravenously infused with MSCs, which were suppressed in their autophagy pathway. Blood and liver samples were collected at different intervals (24, 48 and 72 h) after the transplantation of MSCs. Both the liver enzymes and tissue necrosis levels were evaluated using biochemical and histopathological assessments. The survival rate of the transplanted mice was also recorded during one week. Biochemical and pathological results indicated that 1.5 ml/kg carbon tetrachloride induces ALF in mice. A significant reduction of liver enzymes and necrosis score were observed in autophagy-modulated MSC-transplanted mice compared to sham (with no cell therapy) after 24 h. After 72 h, liver enzymes reached their normal levels in mice transplanted with autophagy-suppressed MSCs. Interestingly, normal histology without necrosis was also observed. Autophagy suppression in MSCs ameliorates their liver regeneration potentials due to paracrine effects and might be suggested as a new strategy for the improvement of cell therapy in ALF.


Cirrhotic cardiomyopathy.
Cirrhotic cardiomyopathy is the term used to describe a constellation of features indicative of abnormal heart structure and function in patients with cirrhosis. These include systolic and diastolic dysfunction, electrophysiological changes, and macroscopic and microscopic structural changes. The prevalence of cirrhotic cardiomyopathy remains unknown at present, mostly because the disease is generally latent and shows itself when the patient is subjected to stress such as exercise, drugs, hemorrhage and surgery. The main clinical features of cirrhotic cardiomyopathy include baseline increased cardiac output, attenuated systolic contraction or diastolic relaxation in response to physiologic, pharmacologic and surgical stress, and electrical conductance abnormalities (prolonged QT interval). In the majority of cases, diastolic dysfunction precedes systolic dysfunction, which tends to manifest only under conditions of stress. Generally, cirrhotic cardiomyopathy with overt severe heart failure is rare. Major stresses on the cardiovascular system such as liver transplantation, infections and insertion of transjugular intrahepatic portosystemic stent-shunts (TIPS) can unmask the presence of cirrhotic cardiomyopathy and thereby convert latent to overt heart failure. Cirrhotic cardiomyopathy may also contribute to the pathogenesis of hepatorenal syndrome. Pathogenic mechanisms of cirrhotic cardiomyopathy are multiple and include abnormal membrane biophysical characteristics, impaired beta-adrenergic receptor signal transduction and increased activity of negative-inotropic pathways mediated by cGMP. Diagnosis and differential diagnosis require a careful assessment of patient history probing for excessive alcohol, physical examination for signs of hypertension such as retinal vascular changes, and appropriate diagnostic tests such as exercise stress electrocardiography, nuclear heart scans and coronary angiography. Current management recommendations include empirical, nonspecific and mainly supportive measures. The exact prognosis remains unclear. The extent of cirrhotic cardiomyopathy generally correlates to the degree of liver insufficiency. Reversibility is possible (either pharmacological or after liver transplantation), but further studies are needed.


Identification of crucial hydrogen-bonding residues for the interaction of herpes simplex virus DNA polymerase subunits via peptide display, mutational, and calorimetric approaches.
The catalytic subunit, Pol, of herpes simplex virus DNA polymerase interacts via its extreme C terminus with the processivity subunit, UL42. This interaction is critical for viral replication and thus a potential target for antiviral drug action. To investigate the Pol-binding region on UL42, we engineered UL42 mutations but also used random peptide display to identify artificial ligands of the Pol C terminus. The latter approach selected ligands with homology to residues 171 to 176 of UL42. Substitution of glutamine 171 with alanine greatly impaired binding to Pol and stimulation of long-chain DNA synthesis by Pol, identifying this residue as crucial for subunit interactions. To study these interactions quantitatively, we used isothermal titration calorimetry and wild-type and mutant forms of Pol-derived peptides and UL42. Each of three peptides corresponding to either the last 36, 27, or 18 residues of Pol bound specifically to UL42 in a 1:1 complex with a dissociation constant of 1 to 2 microM. Thus, the last 18 residues suffice for most of the binding energy, which was due mainly to a change in enthalpy. Substitutions at positions corresponding to Pol residue 1228 or 1229 or at UL42 residue 171 abolished or greatly reduced binding. These residues participate in hydrogen bonds observed in the crystal structure of the C terminus of Pol bound to UL42. Thus, interruption of these few bonds is sufficient to disrupt the interaction, suggesting that small molecules targeting the relevant side chains could interfere with Pol-UL42 binding.


US-Based Food and Agricultural Value Chains and Their Relevance to Healthy Diets.
This article examines the structure and health implications of two industries, chicken and tomatoes, that play prominent roles in US food and agricultural competitiveness. Both industries have become more concentrated over time, with powerful "lead firms" driving geographical, technological, and marketing changes. Overall, a processed food revolution has taken place in agricultural products that transforms the types of food and dietary options available to consumers. The nature of contemporary food and agricultural value chains affects the strategies and policies that can be effectively employed to address major health goals such as improved nutrition, food safety, and food security.


Bone mineral density in young women on methadone substitution.
Little is known about bone mineral density (BMD) in patients with heroin addiction and subsequent methadone substitution. The goal of this study was to compare bone mass density of young HIV-negative women on long-term methadone treatment to a local group of young healthy women. Eleven women (aged 20-29) with previous heroin dependence and current methadone substitution (20-140 mg, median 60, daily) for 1.5-9 (median 3) years were compared to 30 healthy women (aged 20-28). Participants were examined with dual-energy X-ray absorptiometry of the lumbar spine (L2-L4), of the total proximal hip area, and of the femoral neck. Patients and controls had neither current nor lifetime underweight condition, had comparable ages at menarche, and did not differ significantly in current body mass index (21.9 ± 4.0, respectively, 20.5 ± 1.5 kg/m(2)) in spite of a largely unhealthy lifestyle (cigarette, alcohol, and cocaine consumption in patients). Patients' total-hip parameters were marginally lower than those of controls (BMD P = 0.054, T score P = 0.049), whereas the femoral neck and lumbar spine parameters did not differ significantly between the two groups. Long-term methadone substitution in HIV-negative women seems to slightly affect bone mass density.


Decreased LRIG1 in fulvestrant-treated luminal breast cancer cells permits ErbB3 upregulation and increased growth.
ErbB3, a member of the ErbB family of receptor tyrosine kinases, is a potent activator of phosphatidyl inositol-3 kinase (PI3K) and mammalian target of rapamycin (mTOR) signaling, driving tumor cell survival and therapeutic resistance in breast cancers. In luminal breast cancers, ErbB3 upregulation following treatment with the antiestrogen fulvestrant enhances PI3K/mTOR-mediated cell survival. However, the mechanism by which ErbB3 is upregulated in fulvestrant-treated cells is unknown. We found that ErbB3 protein levels and cell surface presentation were increased following fulvestrant treatment, focusing our attention on proteins that regulate ErbB3 at the cell surface, including Nrdp1, NEDD4 and LRIG1. Among these, only LRIG1 correlated positively with ERα, but inversely with ErbB3 in clinical breast cancer data sets. LRIG1, an estrogen-inducible ErbB downregulator, was decreased in a panel of fulvestrant-treated luminal breast cancer cells. Ectopic LRIG1 expression from an estrogen-independent promoter uncoupled LRIG1 from estrogen regulation, thus sustaining LRIG1 and maintaining low ErbB3 levels in fulvestrant-treated cells. An LRIG1 mutant lacking the ErbB3 interaction motif was insufficient to downregulate ErbB3. Importantly, LRIG1 overexpression improved fulvestrant-mediated growth inhibition, whereas cells expressing the LRIG1 mutant were poorly sensitive to fulvestrant, despite effective ERα downregulation. Consistent with these results, LRIG1 expression correlated positively with increased disease-free survival in antiestrogen-treated breast cancer patients. These data suggest that ERα-dependent expression of LRIG1 dampens ErbB3 signaling in luminal breast cancer cells, and by blocking ERα activity with fulvestrant, LRIG1 is decreased thus permitting ErbB3 accumulation, enhanced ErbB3 signaling to cell survival pathways and blunting therapeutic response to fulvestrant.


Is there a 'gut-brain-skin axis'?
Emerging evidence arising from interdisciplinary research supports the occurrence of communication axes between organs, such as the brain-gut or brain-skin axis. The latter is employed in response to stress challenge, along which neurogenic skin inflammation and hair growth inhibition is mediated. We now show that ingestion of a Lactobacillus strain in mice dampens stress-induced neurogenic skin inflammation and the hair growth inhibition. In conclusion, we are introducing a hypothesis, encouraged by our pilot observations and resting upon published prior evidence from the literature, which amalgamates previously proposed partial concepts into a new, unifying model, i.e. the gut-brain-skin axis. This concept suggests that modulation of the microbiome by deployment of probiotics can not only greatly reduce stress-induced neurogenic skin inflammation but even affect a very complex cutaneous phenomenon of (mini-) organ transformation, i.e. hair follicle cycling. These observations raise the intriguing prospect that feeding of just the right kind of bacteria can exert profound beneficial effects on skin homoeostasis, skin inflammation, hair growth and peripheral tissue responses to perceived stress.


Proof of the effect of testosterone on skeletal muscle.
In spite of the widespread abuse of androgenic steroids by athletes and recreational body-builders, the effects of these agents on athletic performance and physical function remain poorly understood. Experimentally induced androgen deficiency is associated with a loss of fat-free mass; conversely, physiologic testosterone replacement of healthy, androgen-deficient men increases fat-free mass and muscle protein synthesis. Testosterone supplementation of HIV-infected men with low testosterone levels and of older men with normally low testosterone concentrations also increases muscle mass. However, we do not know whether physiologic testosterone replacement can improve physical function and health-related quality of life, and reduce the risk of falls and disability in older men or those with chronic illness. Testosterone increases maximal voluntary strength in a dose-dependent manner and thus might improve performance in power-lifting events. However, testosterone has not been shown to improve performance in endurance events. The mechanisms by which testosterone increases muscle mass are not known, but probably involve alterations in the expression of multiple muscle growth regulators.


Response of Glacier and Lake Dynamics in Four Inland Basins to Climate Change at the Transition Zone between the Karakorum And Himalayas.
Inland glacier and lake dynamics on the Tibetan Plateau (TP) and its surroundings over recent decades are good indicators of climate change and have a significant impact on the local water supply and ecosystem. The glacier and lake changes in Karakoram are quite different from those of the Himalayas. The mechanisms of the complex and regionally heterogeneous behavior of the glacier and lake changes between the Karakorum and Himalayas are poorly understood. Based on satellite images and meteorological data of Shiquanhe, Hetian, and Yutian stations, we demonstrate that the overall retreat of glaciers and increase of lake area at the transition zone between the Karakoram and Himalayas (TKH) have occurred since 1968 in response to a significant global climate change. Glacial areas in the Songmuxi Co basin, Zepu Co basin, Mang Co basin and Unnamed Co decreased by -1.98 ± 0.02 km2, -5.39 ± 0.02 km2, -0.01 ± 0.02 km2, and -0.12 ± 0.02 km2 during the study period, corresponding to losses of -1.42%, -2.86%, -1.54%, and -1.57%, respectively. The lake area of the Songmuxi Co, Zepu Co, Mang Co and Unnamed Co increased by 7.57 ± 0.02 km2, 8.53 ± 0.02 km2, 1.35 ± 0.02 km2, and 0.53 ± 0.02 km2, corresponding to growths of 30.22%, 7.55%, 11.39%, and 8.05%, respectively. Increases in temperature was the main reason for glacier retreat, whereas decreases in potential evapotranspiration of lakes, increases in precipitation, and increases in melt water from glaciers and frozen soil all contributed to lake area expansion.


Diagnostic accuracy of lung subtraction iodine mapping CT for the evaluation of pulmonary perfusion in patients with chronic thromboembolic pulmonary hypertension: Correlation with perfusion SPECT/CT.
For treatment of chronic thromboembolic pulmonary hypertension (CTEPH), the evaluation of segmental pulmonary perfusion is important. There are no previous reports about lung subtraction iodine mapping (LSIM) computed tomography (CT) for evaluation of segmental pulmonary perfusion in patients with CTEPH, using lung perfusion SPECT/CT (LPS) as the reference. 50 patients (age, 60.7±16.7years) with known or suspected CTEPH were enrolled in this study. Non-contrast chest CT and CT pulmonary angiography (CTPA) were performed on a 320-detector row CT system. Then, based on a non-rigid registration followed by subtraction of non-contrast images from contrast-enhanced images, color-coded LSIM images were generated. LPS was performed using a SPECT/CT system within a period of 2months, and served as the reference standard. LSIM and CTPA images were evaluated in a blinded manner for the detection of pulmonary perfusion defects on a segment-by-segment basis. The sensitivity, specificity, accuracy, and positive and negative predictive values of LSIM for the detection of segmental perfusion defects were 95% (734/773), 84% (107/127), 93% (841/900), 97% (734/754) and 73% (107/146), respectively, while the corresponding values for CTPA were 65% (505/773), 61% (78/127), 65% (583/900), 91% (505/554) and 23% (78/346). Generalized estimating equations analyses revealed a significantly better performance of LSIM than that of CTPA regarding the sensitivity, accuracy, and positive and negative predictive values (all P<0.0001). LSIM is a feasible technique for segment-based evaluation of pulmonary perfusion in patients with CTEPH, and it provides a significantly higher diagnostic accuracy compared with CTPA.


Using integrating spheres as absorption cells: path-length distribution and application of Beer's law.
We have modeled the path-length distribution in an integrating sphere used as a multipass optical cell for absorption measurements. The measured radiant flux as a function of analyte concentration is nonlinear as a result, deviating from that expected for a single path length. We have developed a full numerical model and introduce a new analytical relationship that describes this behavior for high reflectivity spheres. We have tested both models by measuring the optical absorption of methane at 1651 nm in a 50 mm diameter sphere, with good agreement with experimental data in the absorption range of 0-0.01 cm(-1). Our results compare well with previous work on the temporal response of integrating spheres.


A factorial analysis of the combined effects of hydrogel fabrication parameters on the in vitro swelling and degradation of oligo(poly(ethylene glycol) fumarate) hydrogels.
In this study, a full factorial approach was used to investigate the effects of poly(ethylene glycol) (PEG) molecular weight (MW; 10,000 vs. 35,000 nominal MW), crosslinker-to-macromer carbon-carbon double bond ratio (DBR; 40 vs. 60), crosslinker type (PEG-diacrylate (PEGDA) vs. N,N'-methylene bisacrylamide (MB)), crosslinking extent of incorporated gelatin microparticles (low vs. high), and incubation medium composition (with or without collagenase) on the swelling and degradation characteristics of oligo[(poly(ethylene glycol) fumarate)] (OPF) hydrogel composites as indicated by the swelling ratio and the percentage of mass remaining, respectively. Each factor consisted of two levels, which were selected based on previous in vitro and in vivo studies utilizing these hydrogels for various tissue engineering applications. Fractional factorial analyses of the main effects indicated that the mean swelling ratio and the mean percentage of mass remaining of OPF composite hydrogels were significantly affected by every factor. In particular, increasing the PEG chain MW of OPF macromers significantly increased the mean swelling ratio and decreased the mean percentage of mass remaining by 5.7 ± 0.3 and 17.2 ± 0.6%, respectively. However, changing the crosslinker from MB to PEGDA reduced the mean swelling ratio and increased the mean percentage of mass remaining of OPF composite hydrogels by 4.9 ± 0.2 and 9.4 ± 0.9%, respectively. Additionally, it was found that the swelling characteristics of hydrogels fabricated with higher PEG chain MW or with MB were more sensitive to increases in DBR. Collectively, the main and cross effects observed between factors enables informed tuning of the swelling and degradation properties of OPF-based hydrogels for various tissue engineering applications. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 3477-3487, 2014.


Incidence of catheter-related thrombosis in acute leukemia patients: a comparative, retrospective study of the safety of peripherally inserted vs. centrally inserted central venous catheters.
Central venous catheters are a leading cause of upper-extremity deep vein thrombosis. Concomitant severe thrombocytopenia makes anticoagulation for catheter-related thrombosis (CRT) in patients with acute leukemia (AL) a challenge. Incidence of CRT has been reported to be increased in those with peripherally inserted central catheters (PICC) vs. those with centrally inserted ones (CICC). Our objective is to compare the incidence rate of CRT in leukemia inpatients who received either a PICC vs. CICC. We retrospectively reviewed adult inpatients admitted to hematology wards with a new diagnosis of AL and who received either a PICC or a CICC. Baseline patient and catheter characteristics were recorded. Our primary outcome was the incidence rate of CRT in each group. The secondary outcomes included rates of infectious and mechanical complications. Six hundred sixty-three patients received at least one PICC (338) or CICC (325) insertion. A total of 1331 insertions were recorded, with 82 (11.7 %) and 41 (6.5 %) CRT in the PICC and CICC groups, respectively. The incidence rates were 1.89 and 0.52 per 1000 catheter day in the PICC and CICC groups, respectively. A PICC, when compared to CICC, was a significant risk factor for CRT (sHR 2.5, p < 0.0001). The prevalence and incidence rates of CRT in our AL patients were higher than predicted for a general cancer patient population. These rates were higher in the PICC group compared to the CICC group. We recommend careful consideration of thrombotic and bleeding risks of AL inpatients when choosing a central venous catheter.


Assessment of Corneal Fluorescein Staining in Different Dry Eye Subtypes Using Digital Image Analysis.
To describe a new objective technique of digital image analysis for the quantification and the morphological characterization of corneal staining in the setting of dry eye disease (DED), and to apply it to distinguish Sjögren syndrome (SS) from ocular graft versus-host disease (oGVHD). Slit-lamp photographs of corneal staining obtained from 40 patients with DED (20 with SS and 20 with oGVHD; mean age 60.7 ± 12.3 years) were evaluated. Images were subjectively graded using Oxford and National Eye Institute (NEI) scales, the staining pattern was classified as micropunctate, macropunctate, coalescent, or patch. The corneal staining index (CSI) was calculated automatically using the software ImageJ 1.51s. Particles analysis was used to calculate mean area, circularity, and roundness of staining spots. CSI was significantly correlated with Oxford and NEI scales (respectively Rs = 0.823 and Rs = 0.773; both P < 0.001), and showed a good interobserver reliability (intraclass correlation coefficient [ICC] = 0.988 [95% confidence interval [CI]: 0.978-0.994]). The mean area of staining spots calculated with particles analysis was significantly correlated with the subjective classification of the staining pattern (Rs = 0.550, P < 0.001). The circularity and roundness of staining spots were significantly higher in oGVHD patients compared with SS (respectively, 0.51 ± 0.11 vs. 0.44 ± 0.10, P = 0.040; 0.61 ± 0.03 vs. 0.59 ± 0.02, P = 0.004). Sensitivity and specificity to distinguish oGVHD from SS were respectively 65.0% and 60% for circularity and 80.0% and 70.0% for roundness. The new algorithm showed good reliability and was well correlated with the traditional subjective grading scales. Particles analysis for the objective assessment of the staining pattern may help to differentiate patients with oGVHD from those with SS. The digital image analysis technique may be a reliable alternative to evaluate corneal staining objectively in the clinic and in clinical trials.