Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial.
No treatment options are available for patients with metastatic colorectal cancer that progresses after all approved standard therapies, but many patients maintain a good performance status and could be candidates for further therapy. An international phase 3 trial was done to assess the multikinase inhibitor regorafenib in these patients. We did this trial at 114 centres in 16 countries. Patients with documented metastatic colorectal cancer and progression during or within 3 months after the last standard therapy were randomised (in a 2:1 ratio; by computer-generated randomisation list and interactive voice response system; preallocated block design (block size six); stratified by previous treatment with VEGF-targeting drugs, time from diagnosis of metastatic disease, and geographical region) to receive best supportive care plus oral regorafenib 160 mg or placebo once daily, for the first 3 weeks of each 4 week cycle. The primary endpoint was overall survival. The study sponsor, participants, and investigators were masked to treatment assignment. Efficacy analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT01103323. Between April 30, 2010, and March 22, 2011, 1052 patients were screened, 760 patients were randomised to receive regorafenib (n=505) or placebo (n=255), and 753 patients initiated treatment (regorafenib n=500; placebo n=253; population for safety analyses). The primary endpoint of overall survival was met at a preplanned interim analysis; data cutoff was on July 21, 2011. Median overall survival was 6·4 months in the regorafenib group versus 5·0 months in the placebo group (hazard ratio 0·77; 95% CI 0·64-0·94; one-sided p=0·0052). Treatment-related adverse events occurred in 465 (93%) patients assigned regorafenib and in 154 (61%) of those assigned placebo. The most common adverse events of grade three or higher related to regorafenib were hand-foot skin reaction (83 patients, 17%), fatigue (48, 10%), diarrhoea (36, 7%), hypertension (36, 7%), and rash or desquamation (29, 6%). Regorafenib is the first small-molecule multikinase inhibitor with survival benefits in metastatic colorectal cancer which has progressed after all standard therapies. The present study provides evidence for a continuing role of targeted treatment after disease progression, with regorafenib offering a potential new line of therapy in this treatment-refractory population. Bayer HealthCare Pharmaceuticals.


A randomized trial comparing transurethral resection of the prostate, laser therapy and conservative treatment of men with symptoms associated with benign prostatic enlargement: The CLasP study.
We evaluated the effectiveness of a new technology (noncontact laser therapy) versus that of standard surgery (transurethral prostatic resection) and conservative management for lower urinary tract symptoms associated with benign prostatic enlargement. Men with uncomplicated lower urinary tract symptoms, that is no acute or chronic urinary retention, were randomized to receive laser therapy with a noncontact, side firing neodymium:YAG probe, standard transurethral prostatic resection or conservative management, including monitoring without active intervention, in a large multicenter pragmatic randomized controlled trial called the CLasP study. Primary outcomes were International Prostate Symptom Score (I-PSS), maximum urinary flow rate, a composite measure of success based on I-PSS and maximum urinary flow rate categories, I-PSS quality of life score and post-void residual urine volume. Secondary outcomes included treatment failure, hospital stay and major complications. Followup was 7.5 months after randomization. Intent to treat analysis was done using analysis of covariance, proportional odds models and the Newman-Keuls multiple comparisons procedure. Of symptomatic patients 117, 117 and 106 were randomized to receive laser therapy, transurethral prostatic resection and conservative management, respectively. Baseline characteristics were similar. All primary outcomes indicated that transurethral prostatic resection and laser therapy were superior to conservative management, and resection was superior to laser therapy. As measured by combined improved symptoms and maximum urinary flow, a successful outcome was achieved in 81%, 67% and 15% of men who underwent transurethral prostatic resection, laser therapy and conservative management, respectively. Hospital stay was significantly shorter and complications fewer for laser therapy than for resection but catheters were in place significantly longer. Men treated conservatively did not have deterioration or treatment failure. Laser therapy and transurethral prostatic resection are effective for decreasing lower urinary tract symptoms and post-void residual urine volume as well as improving quality of life and maximum urinary flow in the short term in men presenting with moderate to severe symptoms. Transurethral prostatic resection is superior to laser therapy in terms of effectiveness but some patients may elect laser therapy due to the shorter hospital stay and lower risk of complications. Conservative management may be acceptable and safe in men with lower urinary tract symptoms since we observed no marked deterioration in the short term.


Systematic assessment of multi-gene predictors of pan-cancer cell line sensitivity to drugs exploiting gene expression data.
Background: Selected gene mutations are routinely used to guide the selection of cancer drugs for a given patient tumour. Large pharmacogenomic data sets, such as those by Genomics of Drug Sensitivity in Cancer (GDSC) consortium, were introduced to discover more of these single-gene markers of drug sensitivity. Very recently, machine learning regression has been used to investigate how well cancer cell line sensitivity to drugs is predicted depending on the type of molecular profile. The latter has revealed that gene expression data is the most predictive profile in the pan-cancer setting. However, no study to date has exploited GDSC data to systematically compare the performance of machine learning models based on multi-gene expression data against that of widely-used single-gene markers based on genomics data. Methods: Here we present this systematic comparison using Random Forest (RF) classifiers exploiting the expression levels of 13,321 genes and an average of 501 tested cell lines per drug. To account for time-dependent batch effects in IC 50 measurements, we employ independent test sets generated with more recent GDSC data than that used to train the predictors and show that this is a more realistic validation than standard k-fold cross-validation. Results and Discussion: Across 127 GDSC drugs, our results show that the single-gene markers unveiled by the MANOVA analysis tend to achieve higher precision than these RF-based multi-gene models, at the cost of generally having a poor recall (i.e. correctly detecting only a small part of the cell lines sensitive to the drug). Regarding overall classification performance, about two thirds of the drugs are better predicted by the multi-gene RF classifiers. Among the drugs with the most predictive of these models, we found pyrimethamine, sunitinib and 17-AAG. Conclusions: Thanks to this unbiased validation, we now know that this type of models can predict in vitro tumour response to some of these drugs. These models can thus be further investigated on in vivo tumour models. R code to facilitate the construction of alternative machine learning models and their validation in the presented benchmark is available at http://ballester.marseille.inserm.fr/gdsc.transcriptomicDatav2.tar.gz.


Balancing volume resuscitation and ascites management in cirrhosis.
Patients with cirrhosis have total extracellular fluid overload but central effective circulating hypovolaemia. The resulting neurohumoral compensatory response favours the accumulation of fluids into the peritoneal cavity (ascites) and may hinder renal perfusion (hepatorenal syndrome). Their deranged systemic haemodynamics (hyperdynamic circulatory syndrome) is characterized by elevated cardiac output with decreased systemic vascular resistance and low blood pressure. Molecular and biological mechanisms determining cirrhosis-induced haemodynamic alterations are progressively being elucidated. The need for a goal-directed assessment of volume resuscitation (especially with volumetric techniques) in patients with cirrhosis is becoming more and more evident. The role of fluid expansion with albumin and the use of splanchnic vasopressors in a variety of cirrhosis-related conditions has recently been investigated. The response to fluid loading in patients with advanced cirrhosis is abnormal, primarily resulting in expansion of their noncentral blood volume compartment. Colloid solutions, in particular albumin, are best used in these patients. Albumin may be effective in preventing the haemodynamic derangements associated with large-volume paracentesis (paracentesis-induced circulatory dysfunction), in preventing renal failure during spontaneous bacterial peritonitis and, in association with splanchnic vasopressors, in caring for patients with the hepatorenal syndrome.


Ankle-arm index as a marker of atherosclerosis in the Cardiovascular Health Study. Cardiovascular Heart Study (CHS) Collaborative Research Group.
Peripheral arterial disease measured noninvasively by the ankle-arm index (AAI) is common in older adults, largely asymptomatic, and associated with clinically manifest cardiovascular disease (CVD). The criteria for an abnormal AAI have varied in previous studies. To determine whether there is an inverse dose-response relation between the AAI and clinical CVD, subclinical disease, and risk factors, we examined the relation of the AAI to cardiovascular risk factors, other noninvasive measures of subclinical atherosclerosis using carotid ultrasound, echocardiography and electrocardiography, and clinical CVD. The AAI was measured in 5084 participants > or = 65 years old at the baseline examination of the Cardiovascular Health Study. All subjects had detailed assessment of prevalent CVD, measures of cardiovascular risk factors, and noninvasive measures of disease. Participants were stratified by baseline clinical CVD status and AAI (< 0.8, > or = 0.8 to < 0.9, > or = 0.9 to < 1.0, > or = 1.0 to < 1.5). Analyses tested for a dose-response relation of the AAI with clinical CVD, risk factors, and subclinical disease. The cumulative frequency of a low AAI was 7.4% of participants < 0.8, 12.4% < 0.9, and 23.6% < 1.0. participants with an AAI < 0.8 were more than twice as likely as those with an AAI of 1.0 to 1.5 to have a history of myocardial infarction, angina, congestive heart failure, stroke, or transient ischemic attack (all P < .01). In participants free of clinical CVD at baseline, the AAI was inversely related to history of hypertension, history of diabetes, and smoking, as well as systolic blood pressure, serum creatinine, fasting glucose, fasting insulin, measures of pulmonary function, and fibrinogen level (all P < .01). Risk factor associations with the AAI were similar in men and women free of CVD except for serum total and low-density lipoprotein cholesterol, which were inversely associated with AAI level only in women. Risk factors associated with an AAI of < 1.0 in multivariate analysis included smoking (odds ratio [OR], 2.55), history of diabetes (OR, 3.84), increasing age (OR, 1.54), and nonwhite race (OR, 2.36). In the 3372 participants free of clinical CVD, other noninvasive measures of subclinical CVD, including carotid stenosis by duplex scanning, segmental wall motion abnormalities by echocardiogram, and major ECG abnormalities were inversely related to the AAI (all P < .01). There was an inverse dose-response relation of the AAI with CVD risk factors and subclinical and clinical CVD among older adults. The lower the AAI, the greater the increase in CVD risk; however, even those with modest, asymptomatic reductions in the AAI (0.8 to 1.0) appear to be at increased risk of CVD.


Climate change has likely already affected global food production.
Crop yields are projected to decrease under future climate conditions, and recent research suggests that yields have already been impacted. However, current impacts on a diversity of crops subnationally and implications for food security remains unclear. Here, we constructed linear regression relationships using weather and reported crop data to assess the potential impact of observed climate change on the yields of the top ten global crops-barley, cassava, maize, oil palm, rapeseed, rice, sorghum, soybean, sugarcane and wheat at ~20,000 political units. We find that the impact of global climate change on yields of different crops from climate trends ranged from -13.4% (oil palm) to 3.5% (soybean). Our results show that impacts are mostly negative in Europe, Southern Africa and Australia but generally positive in Latin America. Impacts in Asia and Northern and Central America are mixed. This has likely led to ~1% average reduction (-3.5 X 1013 kcal/year) in consumable food calories in these ten crops. In nearly half of food insecure countries, estimated caloric availability decreased. Our results suggest that climate change has already affected global food production.


Adverse effects of ultraviolet radiation from the use of indoor tanning equipment: time to ban the tan.
The incidence of melanoma skin cancer is increasing rapidly, particularly among young women in the United States. Numerous studies have documented an association between the use of indoor tanning devices and an increased risk of skin cancer, especially in young women. Studies have shown that ultraviolet exposure, even in the absence of erythema or burn, results in DNA damage. Countries and regulatory bodies worldwide have recognized the health risks associated with indoor tanning. In the United States, 32 states have passed legislation to regulate the indoor tanning industry, but there is an urgent need to restrict the use of indoor tanning devices at the federal level. The Food and Drug Administration is currently reviewing the classification of these devices. For all of these reasons, the Food and Drug Administration should prohibit the use of tanning devices by minors and reclassify tanning devices to at least class II to protect the public from the preventable cancers and other adverse effects caused by ultraviolet radiation from indoor tanning.


Use of a Diabetes Self-Assessment Score to Predict Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis.
Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are strongly associated with obesity, insulin resistance, and type 2 diabetes. We recently developed and validated a self-assessment score in the Korean population to identify people at high risk for diabetes. The objective of this study was to evaluate whether the self-assessment risk score for diabetes can also be used to screen for the presence of NAFLD or NASH.The study population included 15,676 subjects (8313 men and 7363 women) over 20 years old who visited the National Health Insurance Service Ilsan Hospital in Korea between 2008 and 2010. Anthropometric, clinical, and laboratory data were analyzed during regular health checkups. Fatty liver disease was diagnosed using ultrasound, discrimination capability was assessed based on the area under the receiver operating characteristic curve (AUC), and evaluation measures, including sensitivity and specificity, were calculated. Multiple logistic analyses were also performed.We calculated a self-assessed risk score for diabetes (range: 0-11), and a cutoff of ≥5 identified 60% (50%) of men (women) at high risk for NAFLD, reflecting a sensitivity of 79% (85%), a specificity of 60% (66%), a positive predictive value (PPV) of 68% (51%), and a negative predictive value (NPV) of 73% (91%), with an AUC of 0.75 (0.82) for men (women). A cutoff point of ≥6 identified 43% (31%) of men (women) at high risk for NASH, reflecting a sensitivity of 80% (86%), a specificity of 64% (75%), a PPV of 30% (28%), and a NPV of 94% (98%), with an AUC of 0.77 (0.86) for men (women). The odds ratios that a 1-point increase in the diabetes risk scores would be associated with an increased risk for NAFLD and NASH were 1.20 [95% confidence interval (CI): 1.16-1.25] and 1.57 (95% CI: 1.49-1.65), respectively, in men, and 1.28 (95% CI: 1.21-1.34) and 1.89 (95% CI: 1.73-2.07), respectively, in women.The present study indicates that our self-assessment risk score for diabetes could be an effective primary screening tool for the presence of NAFLD or NASH.


Gamma' fibrinogen: evaluation of a new assay for study of associations with cardiovascular disease.
Studies of disease associations with gamma' fibrinogen, a newly emerging risk factor for cardiovascular disease, have been hampered by the lack of a standardized and well-characterized assay. We developed an immunometric technique to measure gamma' fibrinogen concentrations in plasma and studied the clinical utility of this test in samples from healthy individuals enrolled in the Framingham Offspring Study and in a separate case/control study of coronary artery disease (CAD). Monoclonal antibody 2.G2.H9, specific for the unique carboxyl terminal peptide of the fibrinogen gamma' chain, was used as capture antibody. Sheep antihuman fibrinogen/horseradish peroxidase conjugate was used for detection, with 3,3',5,5'-tetramethylbenzidine as substrate. We evaluated the linearity, imprecision, analytical specificity, and lower limit of quantification of the assay. We determined the reference interval for gamma' fibrinogen in healthy individuals from the Framingham Offspring Study (n = 2879) and quantified associations between gamma' fibrinogen and cardiovascular disease risk factors. The sensitivity and specificity of gamma' fibrinogen in evaluating CAD patients (n = 133) was determined with ROC curve analysis. The gamma' fibrinogen ELISA had within-run CVs of 13.4% at 0.127 g/L and 4.8% at 0.416 g/L. The limit of quantification at an imprecision of 20% was 0.10 g/L. The reference interval for healthy individuals was 0.088-0.551 g/L. ROC curve analysis of results from patients with CAD yielded an area under the curve of 0.76, with a diagnostic accuracy of 0.78 at a decision threshold of 0.30 g/L. gamma' Fibrinogen shows excellent utility for cardiovascular risk analysis.


[Asthma mortality in the city of São Paulo, Brazil].
To quantify and compare asthma mortality rates as the main cause of death, taking into consideration the following variables: sex, age and seasonality. Data was collected from all death certificates coded 493 of people aged 5 to 34 years in the periods of 1983-5 and 1993-5 in the city of São Paulo, SP, Brazil. Data analysis was performed by directly comparing death rates and identifying the odds ratio trend and directly comparing the numbers of asthma deaths. There was no increase in asthma mortality rates for the study periods. There was no difference between men and women. A greater number of deaths in the age group 20 to 34 years were observed. Seasonality was more evident in the first period studied. Differing from reports in other countries, the results did not show any increase in asthma mortality rates, The variable sex didn't seem to interfere with mortality. Deaths are more frequent among young adults, and their risk may be 9 times greater than that of young children. Deterioration of social and economic issues and health care services and even climatic changes may have been implicated in the absence of seasonality as a risk factor for asthma mortality. The disease by itself is not considered by many health professionals as critical in order to explain the chain of events that lead to death.


Safety evaluation of freehand lateral mass screw fixation in the subaxial cervical spine: evaluation of 1256 screws.
Prospective study. To evaluate the safety of the lateral mass screw (LMS) fixation. LMS fixation has been known to have risk of injury to vertebral artery, nerve root, or facet joints. A consecutive series of 178 patients undergoing planned LMS fixation were studied. Screw fixation was performed using the freehand technique. Entry point of screws was 2-mm medial from the center of the lateral mass. Planned divergent angle of the screw was 30º. Bicortical fixation was tried in all cases. After the surgery, all patients underwent 3-dimensional computed tomographic scan of the cervical spine. We checked the number of screws in each level, divergent angle of the screws, and violation of foramen transversarium (FT), intervertebral foramen, or facet joint by screws. A reliability test was performed. Total 1256 screws were fixed with 269 at C3, 318 at C4, 331 at C5, and 338 screws at C6. Mean divergent angle of the screws were 34.7º/33.1º at C3, 33.9 º/32.1º at C4, 34.7º/32.7º at C5, and 33.6º/30.7º at C6. Incidence of FT violation was 0.876%. FT violation was most common at C6 (6/11 violations). Mean divergent angle in cases of FT violation was 15.0º and was significantly smaller than that of safe cases. There was no injury to vertebral artery. There was no violation of intervertebral foramen. Incidence of facet violation was 1.433%. Seventeen facet violations were within fusion segment. Only 1 screw violated healthy facet. Facet violation was most common at C3 (12/18 violations). LMS fixation is a safe stabilizing technique with very low incidence of violation of FT, intervertebral foramen, and facet. There is a possibility of FT violation if the divergent angle was small. FT violation was most common at C6. Facet violation was most common at C3.


Predictors of quality of life in people with Parkinson's disease: evidence for both domain specific and general relationships.
To assess the determinants of health-related quality of life (HrQoL) in people with Parkinson's disease (PD). Eighty-one people with a diagnosis of idiopathic PD took part in a cross-sectional questionnaire-based study. Measures were collected in a community setting and included established determinants of HrQoL (demographic, clinical and cognitive variables) but also included a wide range of mental health variables (depression, anxiety and stress) and, for the first time, positive psychological functioning (optimism and self-esteem). HrQoL was measured by the full version of the Parkinson's Disease Questionnaire (PDQ-39) which includes eight domains of functioning. Mental health measures (depression, anxiety and stress) were more influential than any other block of determinants and influenced a broader array of HrQoL domains including physical ones. There was some evidence of domain-specific relationships, e.g. between physical determinants and the more physically-oriented HrQoL domains, and between mental health determinants and emotional well-being. However, cognitive ability did not influence the HrQoL domain of cognitive impairment. The contribution of a multi-disciplinary approach is crucial given the many variables which affect HrQoL; in particular, significant overall improvements on HrQoL are unlikely if only physical rehabilitation is offered. Rehabilitation is likely to be beneficial in terms of HrQoL only if it is planned and delivered holistically. Implications for Rehabilitation Interventions to improve physical function may have only limited impact on quality of life and might be limited to more physical HrQoL domains. Psychological interventions have the potential to improve quality of life over a wider range of both emotional and physical HrQoL domains. Clinician-measured level of functioning does not necessarily translate into patient-perceived levels of functional ability and relatively small objective decreases in ability can be appraised much more significantly disabling by people with PD.


Cardiac glycoside downregulates NHE3 activity and expression in LLC-PK1 cells.
Ouabain, a cardiotonic steroid and a specific inhibitor of the Na(+)-K(+)-ATPase, has been shown to significantly inhibit transcellular Na(+) transport without altering the intracellular Na(+) concentration ([Na(+)](i)) in the epithelial cells derived from the renal proximal tubules. We therefore studied whether ouabain affects the activity and expression of Na(+)/H(+) exchanger isoform 3 (NHE3) representing the major route of apical Na(+) reabsorption in LLC-PK(1) cells. Chronic basolateral, but not apical, exposure to low-concentration ouabain (50 and 100 nM) did not change [Na(+)](i) but significantly reduced NHE3 activity, NHE3 protein, and mRNA expression. Inhibition of c-Src or phosphoinositide 3-kinase (PI3K) with PP2 or wortmannin, respectively, abolished ouabain-induced downregulation of NHE3 activity and mRNA expression. In caveolin-1 knockdown LLC-PK(1) cells, ouabain failed to downregulate NHE3 mRNA expression and NHE3 promoter activity. Ouabain response elements were mapped to a region between -450 and -1,194 nt, where decreased binding of thyroid hormone receptor (TR) and Sp1 to their cognate cis-elements was documented in vitro and in vivo by protein/DNA array analysis, EMSA, supershift, and chromatin immunoprecipitation. These data suggest that, in LLC-PK(1) cells, ouabain-induced signaling through the Na(+)-K(+)-ATPase-Src pathway results in decreased Sp1 and TR DNA binding activity and consequently in decreased expression and activity of NHE3. These novel findings may represent the underlying mechanism of cardiotonic steroid-mediated renal compensatory response to volume expansion and/or hypertension.


Stage-specific control of oligodendrocyte survival and morphogenesis by TDP-43.
Generation of oligodendrocytes in the adult brain enables both adaptive changes in neural circuits and regeneration of myelin sheaths destroyed by injury, disease, and normal aging. This transformation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes requires processing of distinct mRNAs at different stages of cell maturation. Although mislocalization and aggregation of the RNA-binding protein, TDP-43, occur in both neurons and glia in neurodegenerative diseases, the consequences of TDP-43 loss within different stages of the oligodendrocyte lineage are not well understood. By performing stage-specific genetic inactivation of Tardbp in vivo, we show that oligodendrocyte lineage cells are differentially sensitive to loss of TDP-43. While OPCs depend on TDP-43 for survival, with conditional deletion resulting in cascading cell loss followed by rapid regeneration to restore their density, oligodendrocytes become less sensitive to TDP-43 depletion as they mature. Deletion of TDP-43 early in the maturation process led to eventual oligodendrocyte degeneration, seizures, and premature lethality, while oligodendrocytes that experienced late deletion survived and mice exhibited a normal lifespan. At both stages, TDP-43-deficient oligodendrocytes formed fewer and thinner myelin sheaths and extended new processes that inappropriately wrapped neuronal somata and blood vessels. Transcriptional analysis revealed that in the absence of TDP-43, key proteins involved in oligodendrocyte maturation and myelination were misspliced, leading to aberrant incorporation of cryptic exons. Inducible deletion of TDP-43 from oligodendrocytes in the adult central nervous system (CNS) induced the same progressive morphological changes and mice acquired profound hindlimb weakness, suggesting that loss of TDP-43 function in oligodendrocytes may contribute to neuronal dysfunction in neurodegenerative disease.


A digitally supported home-based exercise training program and dietary protein intervention for community dwelling older adults: protocol of the cluster randomised controlled VITAMIN trial.
Increased physical activity and dietary protein intake are promising interventions to prevent or treat the age-related decline in physical performance in older adults. There are well-controlled exercise as well as dietary intervention studies that show beneficial effects on physical performance in older adults. In practice, however, weekly group based exercise or nutritional programs may not be as effective. To optimise these exercise programs for community dwelling older adults, a digitally supported and personalised home-based exercise training program has been designed aiming to improve physical performance in older adults. In addition, a protein intervention in combination with the training program may further improve physical performance in older adults. The VITAMIN study will be a cluster randomised controlled trial with three parallel arms. In total, 240 community dwelling older adults (≥ 55 years) participating in weekly group exercise are randomly allocated into: 1) regular weekly exercise program (Control group, n = 80), 2) digitally supported personalised home-based exercise training program group (VITA group, n = 80) and 3) digitally supported personalised home-based exercise training program group plus dietary protein counselling (VITA-Pro group, n = 80). The VITAMIN study aims to evaluate effectiveness of the digitally supported personalised home-based exercise training program as well as the additional value of dietary protein on physical performance after 6 months. In addition, a 12 month follow-up measurement will assess the retaining effect of the interventions. Primary outcome is physical performance measured by the Modified Physical Performance Test (M-PPT) and relevant secondary and observational outcomes include habitual physical activity and dietary intake, body composition, cognitive performance, quality of life, compliance and tablet usage. Data will be analysed by Linear Mixed Models. To our knowledge, the VITAMIN study is the first study that investigates the impact of home-based exercise, protein intake as well as use of persuasive technology in the population of community dwelling older adults. NL56094.029.16 / NTR ( TC = 5888 ; registered 03-06-2016).


Diffraction of radiation of any state of spatial coherence on media with periodic structure.
A general formula is derived for the spectral density distribution in the far zone, produced by the diffraction of a beam of any state of spatial coherence on a medium with a spatially periodic structure. The formula may be used to determine the structure of crystals from the diffraction of partially coherent x-ray beams.


Sequence analysis of bacterial DNA in the colon and stomach of the Tyrolean Iceman.
The male human body found in an Alpine glacier on September 19, 1991 ("Tyrolean Iceman") has, for the first time in history, given scientists a chance to perform detailed anatomical, histological, and molecular investigations on the organs of a person from the Neolithic Age (5350-5100 B.P.). In the present study, tissue samples aseptically taken from the stomach and the colon of the mummy were utilized for DNA extraction, and the DNA was PCR-amplified, using primer pairs designed to bind to fragments of the 16s ribosomal RNA gene (16s rDNA) of a broad range of bacteria. The PCR products were cloned in plasmid vectors, and the recombinant clones (amplicons) were sequenced. The sequence data were finally used for scanning data libraries containing the corresponding sequences of present-day bacteria, to infer the putative ecophysiology of the ancient ones. The same procedure was repeated on some fragments of grass from the clothing found near the corpse. These fragments were taken as a control of the microbiological situation of the glacier. The results show that the flora of the Iceman's stomach is entirely composed of Burkholderia pickettii, an organism commonly found in aquatic habitats. The colon, on the other hand, contains several members of the fecal flora of humans, such as Clostridium perfringens, C. ghonii, C. sordellii, Eubacterium tenue, and Bacteroides sp. The Iceman's colon, however, was found to contain, rather unexpectedly, also some members of the genus Vibrio. The results are discussed in light of what is known about the preservation of microbial DNA at the Iceman's site and of previous parasitological studies performed on the Iceman himself and on human coprolites.


Apoptotic mechanisms during competition of ribosomal protein mutant cells: roles of the initiator caspases Dronc and Dream/Strica.
Heterozygosity for mutations in ribosomal protein genes frequently leads to a dominant phenotype of retarded growth and small adult bristles in Drosophila (the Minute phenotype). Cells with Minute genotypes are subject to cell competition, characterized by their selective apoptosis and removal in mosaic tissues that contain wild-type cells. Competitive apoptosis was found to depend on the pro-apoptotic reaper, grim and head involution defective genes but was independent of p53. Rp/+ cells are protected by anti-apoptotic baculovirus p35 expression but lacked the usual hallmarks of 'undead' cells. They lacked Dronc activity, and neither expression of dominant-negative Dronc nor dronc knockdown by dsRNA prevented competitive apoptosis, which also continued in dronc null mutant cells or in the absence of the initiator caspases dredd and dream/strica. Only simultaneous knockdown of dronc and dream/strica by dsRNA was sufficient to protect Rp/+ cells from competition. By contrast, Rp/Rp cells were also protected by baculovirus p35, but Rp/Rp death was dronc-dependent, and undead Rp/Rp cells exhibited typical dronc-dependent expression of Wingless. Independence of p53 and unusual dependence on Dream/Strica distinguish competitive cell death from noncompetitive apoptosis of Rp/Rp cells and from many other examples of cell death.


An Exploratory Study of "Selfitis" and the Development of the Selfitis Behavior Scale.
In 2014, stories appeared in national and international media claiming that the condition of "selfitis" (the obsessive taking of selfies) was to be classed as a mental disorder by the American Psychiatric Association and that the condition could be borderline, acute, or chronic. However, the stories were a hoax but this did not stop empirical research being carried out into the concept. The present study empirically explored the concept and collected data on the existence of selfitis with respect to the three alleged levels (borderline, acute, and chronic) and developed the Selfitis Behavior Scale (SBS). Initially, focus group interviews with 225 Indian university students were carried out to generate potential items for the SBS. The SBS was then validated using 400 Indian university students via exploratory factor analysis (EFA). Six factors were identified in the EFA comprising environmental enhancement, social competition, attention seeking, mood modification, self-confidence, and social conformity. The findings demonstrate that the SBS appears to be a reliable and valid instrument for assessing selfitis but that confirmatory studies are needed to validate the concept more rigorously.


Modaline sulfate promotes Oct4 expression and maintains self-renewal and pluripotency of stem cells through JAK/STAT3 and Wnt signaling pathways.
Stem cells have been extensively explored for a variety of regenerative medical applications and they play an important role in clinical treatment of many diseases. However, the limited amount of stem cells and their tendency to undergo spontaneous differentiation upon extended propagation in vitro restrict their practical application. Octamer-binding transcription factor-4 (Oct4), a transcription factor belongs to the POU transcription factor family Class V, is fundamental for maintaining self-renewal ability and pluripotency of stem cells. In the present study, we used the previously constructed luciferase reporters driven by the promoter and 3'-UTR of Oct4 respectively to screen potential activators of Oct4. Colony formation assay, sphere-forming ability assay, alkaline phosphatase (AP) activity assay and teratoma-formation assay were used to assess the role of modaline sulfate (MDLS) in promoting self-renewal and reinforcing pluripotency of P19 cells. Immunofluorescence, RT-PCR, and western blotting were used to measure expression changes of stem-related genes and activation of related signaling pathways. We screened 480 commercially available small-molecule compounds and discovered that MDLS greatly promoted the expression of Oct4 at both mRNA and protein levels. Moreover, MDLS significantly promoted the self-renewal capacity of P19 cells. Also, we observed that the expression of pluripotency markers and alkaline phosphatase (AP) increased significantly in MDLS-treated colonies. Furthermore, MDLS could promote teratoma formation and enhanced differentiation potential of P19 cells in vivo. In addition, we found that in the presence of LIF, MDLS could replace feeder cells to maintain the undifferentiated state of OG2-mES cells (Oct4-GFP reporter gene mouse embryonic stem cell line), and the MDLS-expanded OG2-mES cells showed an elevated expression levels of pluripotency markers in vitro. Finally, we found that MDLS promoted Oct4 expression by activating JAK/STAT3 and classic Wnt signaling pathways, and these effects were reversed by treatment with inhibitors of corresponding signaling pathways. These findings demonstrated, for the first time, that MDLS could maintain self-renewal and pluripotency of stem cells.


Preparation and anti-HIV activities of aurintricarboxylic acid fractions and analogues: direct correlation of antiviral potency with molecular weight.
Aurintricarboxylic acid (ATA) was fractionated by a combination of dialysis, ultrafiltration, and gel permeation chromatography. The number average and weight average molecular weights of the ATA fractions were determined by the universal calibration method. The sulfonic acid analogue of ATA was prepared and separated in high and low molecular weight fractions. The phosphonic acid analogue of ATA was also synthesized. All of the ATA fractions were tested for prevention of the cytopathic effect of HIV-1 and HIV-2 in MT-4 cell culture as well as against HIV-1 in CEM cell culture. The abilities of the fractions and analogues to inhibit syncytium formation between HIV-1- and HIV-2-infected HUT-78 cells and uninfected MOLT-4 cells were evaluated. In addition, the fractions and analogues were tested for cytotoxicity in mock-infected MT-4 cells, prevention of the binding of the OKT4A monoclonal antibody to the CD4 receptor, inhibition of the binding of anti-gp120 monoclonal antibody to gp120, inhibition of attachment of HIV-1 virions to MT-4 cells, and inhibition of HIV-1 reverse transcriptase. In all of these assays except cytotoxicity, there was a correlation of potency with molecular weight. The higher the molecular weight, the higher the activity. Several of the lower molecular weight fractions of ATA, which bound to gp120 but not to CD4, prevented HIV-1 and HIV-2 cytopathicity. A similar profile was observed for the phosphonic acid analogue of ATA and the lower molecular weight fraction of the sulfonic acid analogue. The results on the ATA fractions indicate that the binding of ATA to gp120 in the absence of CD4 binding is sufficient for anti-HIV activity. The active compounds bind more avidly to gp120 than to CD4. The anti-HIV activity of the ATA fractions is due to inhibition of virus binding due to an interference with the gp120-CD4 interaction.


A novel unsaturated β-glucuronyl hydrolase involved in ulvan degradation unveils the versatility of stereochemistry requirements in family GH105.
Ulvans are cell wall matrix polysaccharides in green algae belonging to the genus Ulva. Enzymatic degradation of the polysaccharide by ulvan lyases leads to the production of oligosaccharides with an unsaturated β-glucuronyl residue located at the non-reducing end. Exploration of the genomic environment around the Nonlabens ulvanivorans (previously Percicivirga ulvanivorans) ulvan lyase revealed a gene highly similar to known unsaturated uronyl hydrolases classified in the CAZy glycoside hydrolase family 105. The gene was cloned, the protein was overexpressed in Escherichia coli, and enzymology experiments demonstrated its unsaturated β-glucuronyl activity. Kinetic analysis of purified oligo-ulvans incubated with the new enzyme showed that the full substrate specificity is attained by three subsites that preferentially bind anionic residues (sulfated rhamnose, glucuronic/iduronic acid). The three-dimensional crystal structure of the native enzyme reveals that a trimeric organization is required for substrate binding and recognition at the +2 binding subsite. This novel unsaturated β-glucuronyl hydrolase is part of a previously uncharacterized subgroup of GH105 members and exhibits only a very limited sequence similarity to known unsaturated β-glucuronyl sequences previously found only in family GH88. Clan-O formed by families GH88 and GH105 was singular in the fact that it covered families acting on both axial and equatorial glycosidic linkages, respectively. The overall comparison of active site structures between enzymes from these two families highlights how that within family GH105, and unlike for classical glycoside hydrolysis, the hydrolysis of vinyl ether groups from unsaturated saccharides occurs independently of the α or β configuration of the cleaved linkage.


A new approach to inhibit human β-tryptase by protein surface binding of four-armed peptide ligands with two different sets of arms.
A series of six new tetravalent ligands (1-6) with two different sets of arms bind to the surface of β-tryptase, a tetrameric enzyme with an A(2)B(2) arrangement of its four monomers and two different binding sites on its protein surface (as suggested by a docking study). Besides proteinogenic amino acids also the guanidiniocarbonyl pyrrole cation (abbreviated as GCP), as an artificial arginine analog, was introduced into the arms of the ligands to investigate its influence on protein surface binding and enzyme inhibition. Furthermore, four ligands (7-10) with four identical arms also containing the GCP group were additionally synthesized to study the influence of the GCP moiety on the inhibition properties compared to related ligands previously identified by us in earlier work. The best ligand from this new series (RWKG)(2)(GCP-LFG)(2) (6) indeed contains the artificial GCP group and with a K(i)-value of 67 nM is two orders of magnitude more efficient than the analogous ligand (RWKG)(2)(RLFG)(2) (1) derived solely from proteinogenic amino acids. Hence, four-armed ligands with two different arms are indeed efficient inhibitors for β-tryptase and the artificial GCP group can improve the binding affinity of this type of ligand to the protein, demonstrating the advantage of tailor-made binding motifs to increase affinity.


A role for MIR828 in pineapple fruit development.
Chen et al. ( Nature Genet. 51: 1549-1558; Oct. 2019) sequenced Ananas comosus var. bracteatus accession CB5, cultivated for its bright pink-to-red colored fruit, and yellow-fleshed A. comosus accession F153, reporting an improved F153 reference assembly while annotating MICRORNA (MIRNA) loci and gene family expressions relevant to lignin and anthocyanin biosynthesis. An independent article (Xiong et al.Sci. Rep. 8: 1947; 2018) reported var. bracteatus MIRNAs but not MIR828, a negative regulator of anthocyanin and polyphenolics biosynthesis by targeting MYB transcription factors associated with UV light- and sugar-signaling in dicots. MIR828 has been reported in gymnosperms, Amborella (sister to flowering plants), and basal monocot orders Liliales, Asparagales, Zingiberales, Arecales, but not in the Poales, a sister order comprising grasses and ~3,000 species of bromeliads including pineapple. Here I show MIR828 exists in pineapple and directs post-transcriptional gene silencing of mRNAs encoding MYB family members with inferred function to regulate the conspicuous red fruit trait in var. bracteatus. MIR828 plesiomorphy (an ancient basal trait) may shed light on monocot apomorphic fruit development, postulated for 21 monocot families with fleshy fruits as due to homoplasy/convergence driven by tropical climate and/or enticements to vertebrate endozoic seed dispersers.


The influence of cell interactions and tissue mass on differentiation of sea urchin mesomeres.
The developmental potential of different blastomeres of the sea urchin embryo was re-examined. We have employed a new method to isolate substantial numbers of different kinds of blastomeres from 16-cell-stage embryos, and we have used newly available molecular markers to analyze possible vegetal differentiation. We have found that, while isolated mesomere pairs behave according to the classical expectations and develop into ectodermal vesicles, there is a clear effect of reaggregating two or more mesomere pairs. They survive better in long-term culture and, after prolonged periods, they display an astonishing ability to express vegetal differentiation. We also combined mesomeres with stained micromeres or macromeres from the vegetal hemisphere. Although induction of guts and spicules was observed, there was little if any effect of varying the ratio of different blastomeres on the kinds of differentiation obtained.


Spiritual healing in the treatment of rheumatoid arthritis: an exploratory single centre, parallel-group, double-blind, three-arm, randomised, sham-controlled trial.
Our objective was to investigate the efficacy of "energy/spiritual healing" in rheumatoid arthritis (RA). Eligible patients were women with RA on stable medication. The design was a randomised, blinded, sham-controlled trial; the third group included an external unblinded control of the natural course of RA. Participants in both groups received 8 sessions with "perceived healing" over 21 weeks with 8 weeks of follow-up. Active healing (AH) treatment comprised healing with no physical contact, and sham healing (SH) included exactly the same healing with a sham healer. During intervention, participants wore hearing protectors and were blindfolded. No healing (NH) only had their outcomes assessed. Coprimary outcomes were disease activity score (DAS) for 28 joints and Doppler ultrasound. All 96 patients randomised were handled as the intention-to-treat population, using a baseline-carried forward approach to replace the missing data. Eighty-two (85%) participants completed the 29-week trial. At end point (week 29), mean difference in DAS28 between AH versus SH was statistically but not clinically significant in favour of AH (0.62 DAS28 points; 95% CI: 0.13 to 1.11; P = 0.014), while no differences between groups occurred in Doppler ultrasound. There are no clear physiological or psychological explanations for the findings in this tightly controlled study. The trial data indicates a need for independent replication.


Fuzzy cognitive mapping and soft models of indigenous knowledge on maternal health in Guerrero, Mexico.
Effective health care requires services that are responsive to local needs and contexts. Achieving this in indigenous settings implies communication between traditional and conventional medicine perspectives. Adequate interaction is especially relevant for maternal health because cultural practices have a notable role during pregnancy, childbirth and the postpartum period. Our work with indigenous communities in the Mexican state of Guerrero used fuzzy cognitive mapping to identify actionable factors for maternal health from the perspective of traditional midwives. We worked with twenty-nine indigenous women and men whose communities recognized them as traditional midwives. A group session for each ethnicity explored risks and protective factors for maternal health among the Me'phaa and Nancue ñomndaa midwives. Participants mapped factors associated with maternal health and weighted the influence of each factor on others. Transitive closure summarized the overall influence of each node with all other factors in the map. Using categories set in discussions with the midwives, the authors condensed the relationships with thematic analysis. The composite map combined categories in the Me'phaa and the Nancue ñomndaa maps. Traditional midwives in this setting attend to pregnant women's physical, mental, and spiritual conditions and the corresponding conditions of their offspring and family. The maps described a complex web of cultural interpretations of disease - "frío" (cold or coldness of the womb), "espanto" (fright), and "coraje" (anger) - abandonment of traditional practices of self-care, women's mental health, and gender violence as influential risk factors. Protective factors included increased male involvement in maternal health (having a caring, working, and loving husband), receiving support from traditional healers, following protective rituals, and better nutrition. The maps offer a visual language to present and to discuss indigenous knowledge and to incorporate participant voices into research and decision making. Factors with higher perceived influence in the eyes of the indigenous groups could be a starting point for additional research. Contrasting these maps with other stakeholder views can inform theories of change and support co-design of culturally appropriate interventions.


Impact of treatment characteristics on response of different breast cancer phenotypes: pooled analysis of the German neo-adjuvant chemotherapy trials.
Pathological complete response (pCR) to neoadjuvant treatment correlates with outcome in breast cancer. We determined whether characteristics of neoadjuvant therapy are associated with pCR. We used multi-level models, which accounted for heterogeneity in pCR across trials and trial arms, to analyze individual patient data from 3332 women included in 7 German neoadjuvant trials with uniform protocols. PCR was associated with an increase in number of chemotherapy cycles (odds ratio [OR] 1.2 for every two additional cycles; P = 0.009), with higher cumulative anthracycline doses (OR 1.6; P = 0.002), higher cumulative taxane doses (OR 1.6; P = 0.009), and with capecitabine containing regimens (OR 1.62; P = 0.022). Association of pCR with increase in number of cycles appeared more pronounced in hormone receptor (HR)-positive tumors (OR 1.35) than in HR-negative tumors (OR 1.04; P for interaction = 0.046). Effect of anthracycline dose was particularly pronounced in HER2-negative tumors (OR 1.61), compared to HER2-positive tumors (OR 0.83; P for interaction = 0.14). Simultaneous trastuzumab treatment in HER2-positive tumors increased odds of pCR 3.2-fold (P < 0.001). No association of pCR and number of trastuzumab cycles was found (OR 1.20, P = 0.39). Dosing characteristics appear important for successful treatment of breast cancer. Longer treatment, higher cumulative doses of anthracyclines and taxanes, and the addition of capecitabine and trastuzumab are associated with better response. Tailoring according to breast cancer phenotype might be possible: longer treatment in HR-positive tumors, higher cumulative anthracycline doses for HER2-negative tumors, shorter treatment at higher cumulative doses for triple-negative tumors, and limited number of preoperative trastuzumab cycles in HER2-positive tumors.


Histamine receptors in isolated guinea pig duodenal muscle: H3 receptors inhibit cholinergic neurotransmission.
A series of histamine H3 receptor agonists and the H3 receptor antagonist thioperamide were tested in the isolated guinea pig duodenum, to investigate the role of this new receptor subtype in the intestinal contractility. At the same time the selectivity of the different compounds for the various histamine receptor subtypes was investigated. In the presence of famotidine (10(-6) M) and thioperamide (10(-5) M), histamine, N alpha-methylhistamine (NMH) and (R)-alpha-methylhistamine (alpha-MH) exerted a concentration-dependent contractile effect through activation of H1 receptors; the ratio of potency was histamine = NMH greater than alpha-MH (this last compound was approximately 500 times less potent). In the presence of pyrilamine (10(-6) M) and thioperamide (10(-5) M), histamine, dimaprit and impromidine caused a slight contractile effect, showing a high degree of tachyphylaxis; this effect was abolished by tetrodotoxin (10(-6) M) and by famotidine (10(-6) M). alpha-MH was ineffective up to 10(-4) M. The H2 receptor agonists dimaprit (10(-4) to 10(-3) M) and impromidine (10(-6) to 10(-5) M) caused a relaxant effect on the contraction elicited by acetylcholine (ACh), BaCl2 and electrical stimulation. This effect, which was unaffected by famotidine, was not mimicked by alpha-MH and not reversed by thioperamide (10(-5) M). In the presence of pyrilamine (109-6) M) and famotidine (10(-6) M), histamine, NMH and alpha-MH inhibited the twitch responses to electrical stimulation, with EC50 values of 1.17 x 10(-7), 6.76 x 10(-8) and 2.45 x 10(-8) M, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


Emerging anti-inflammatory strategies for COPD.
The hallmark of chronic obstructive pulmonary disease (COPD) is an enhanced or abnormal inflammatory immune response of the lungs to inhaled particles and gases, usually from cigarette smoke, characterised by increased numbers of neutrophils, activated macrophages and activated T-lymphocytes (Tc1 and Th1 cells). Therefore, suppression of the inflammatory response is a logical approach to the treatment of COPD. Despite the inflammatory nature of COPD, currently available anti-inflammatory therapies provide little or no benefit in COPD patients and may have detrimental effects. For this reason, there is an urgent need to discover effective and safe anti-inflammatory treatments that might prevent the relentless progression of the disease. In recent years, attention has largely been focused on inhibition of recruitment and activation of inflammatory cells, and on antagonism of their products. In this review, we put together a summary of the state-of-the-art development of clearly and/or potentially useful anti-inflammatory strategies in COPD.


Single-molecule diffusometry reveals the nucleotide-dependent oligomerization pathways of Nicotiana tabacum Rubisco activase.
Oligomerization plays an important role in the function of many proteins, but a quantitative picture of the oligomer distribution has been difficult to obtain using existing techniques. Here we describe a method that combines sub-stoichiometric labeling and recently developed single-molecule diffusometry to measure the size distribution of oligomers under equilibrium conditions in solution, one molecule at a time. We use this technique to characterize the oligomerization behavior of Nicotiana tabacum (Nt) Rubisco activase (Nt-Rca), a chaperone-like AAA-plus ATPase essential in regulating carbon fixation during photosynthesis. We directly observed monomers, dimers, and a tetramer/hexamer mixture and extracted their fractional abundance as a function of protein concentration. We show that the oligomerization pathway of Nt-Rca is nucleotide dependent: ATPγS binding strongly promotes tetramer/hexamer formation from dimers and results in a preferred tetramer/hexamer population for concentrations in the 1-10 μM range. Furthermore, we directly observed dynamic assembly and disassembly processes of single complexes in real time and from there estimated the rate of subunit exchange to be ∼0.1 s-1 with ATPγS. On the other hand, ADP binding destabilizes Rca complexes by enhancing the rate of subunit exchange by >2 fold. These observations provide a quantitative starting point to elucidate the structure-function relations of Nt-Rca complexes. We envision the method to fill a critical gap in defining and quantifying protein assembly pathways in the small-oligomer regime.


Neural mechanisms underlying melodic perception and memory for pitch.
The neural correlates of music perception were studied by measuring cerebral blood flow (CBF) changes with positron emission tomography (PET). Twelve volunteers were scanned using the bolus water method under four separate conditions: (1) listening to a sequence of noise bursts, (2) listening to unfamiliar tonal melodies, (3) comparing the pitch of the first two notes of the same set of melodies, and (4) comparing the pitch of the first and last notes of the melodies. The latter two conditions were designed to investigate short-term pitch retention under low or high memory load, respectively. Subtraction of the obtained PET images, superimposed on matched MRI scans, provides anatomical localization of CBF changes associated with specific cognitive functions. Listening to melodies, relative to acoustically matched noise sequences, resulted in CBF increases in the right superior temporal and right occipital cortices. Pitch judgments of the first two notes of each melody, relative to passive listening to the same stimuli, resulted in right frontal-lobe activation. Analysis of the high memory load condition relative to passive listening revealed the participation of a number of cortical and subcortical regions, notably in the right frontal and right temporal lobes, as well as in parietal and insular cortex. Both pitch judgment conditions also revealed CBF decreases within the left primary auditory cortex. We conclude that specialized neural systems in the right superior temporal cortex participate in perceptual analysis of melodies; pitch comparisons are effected via a neural network that includes right prefrontal cortex, but active retention of pitch involves the interaction of right temporal and frontal cortices.


Forgetting constrains the emergence of cooperative decision strategies.
Theoretical studies of cooperative behavior have focused on decision strategies that depend on a partner's last choices. The findings from this work assume that players accurately remember past actions. The kind of memory that these strategies employ, however, does not reflect what we know about memory. Here, we show that human memory may not meet the requirements needed to use these strategies. When asked to recall the previous behavior of simulated partners in a cooperative memory task, participants performed poorly, making errors in 10-24% of the trials. Participants made more errors when required to track more partners. We conducted agent-based simulations to evaluate how well cooperative strategies cope with error. These simulations suggest that, even with few errors, cooperation could not be maintained at the error rates demonstrated by our participants. Our results indicate that the strategies typically used in the study of cooperation likely do not reflect the underlying cognitive capacities used by humans and other animals in social interactions. By including unrealistic assumptions about cognition, theoretical models may have overestimated the robustness of the existing cooperative strategies. To remedy this, future models should incorporate what we know about cognition.


Cortisol influences the ontogeny of both alpha- and beta-subunits of the cardiac sodium channel in fetal sheep.
During development, the heart has to adapt to changes in shape, size and, at birth, to significant changes in arterial pressure. The orderly contraction of the heart is dependent on the coordinated expression of ion channels at appropriate densities in individual cardiac myocytes. The present study demonstrated that the expression of the alpha-subunit of the cardiac sodium channel, SCN5a, was high at mid gestation but then decreased until 10 days before birth before increasing again. Whereas the beta-subunit, SCN1b, gradually increased in expression towards partum, there was no detectable expression of SCN3b at any gestational time point. Fetal adrenalectomy prior to the normal prepartum surge in cortisol caused a reduction in expression of SCN1b and a 7.0 kb transcript of SCN5a, but not the major 8.5 kb transcript. Conversely, cortisol infusion into immature fetuses precociously increased expression levels of SCN1b and the SCN5a 7.0 kb transcript. The results show that cortisol regulates cardiac SCN gene expression in fetal sheep during late gestation. These findings could have implications for the aetiology of sudden infant death syndrome and for the intrauterine programming of adult cardiovascular disease.


Establishment and characterization of human signet ring cell gastric carcinoma cell lines with amplification of the c-myc oncogene.
Two unique human signet ring cell gastric carcinoma cell lines (designated HSC-39 and HSC-40A) were established in vitro from the ascites of a 54-year-old male patient. Both cell lines were biologically quite similar, grew in vitro in suspension with a population doubling time of 28-30 h, and had cytological features of mucinous epithelial tumor cells. They formed colonies in soft agar, with a cloning efficiency of 0.8-1.0%. Ultrastructurally, numerous granules were observed in the cytoplasm, suggesting secretory activity. The frequent presence of desmosome and the tight junction at the cell boundary certifies the epithelial origin of the lines. Immunocytochemistry and radioimmunoassay showed production of tumor marker antigens (carcinoembryonic antigen, CA 19-9, and sialyl-Lex-i) and gastrin in both lines. These lines were transplantable in athymic BALB/c nude mice. The histopathology of each line growing in athymic BALB/c nude mice was similar to that of the original tumor. The karyotype of the cells was highly aberrant with structural and numerical changes. The presence of numerous double minute chromosomes and loss of the 13 chromosome and Y-chromosome characterize these lines. In addition, the amplified c-myc oncogene (16-32-fold) was found in both cell lines and original ascitic tumor cells. Overexpression of the c-myc mRNA was noted. These cell lines may be a useful tool, providing both in vivo and in vitro systems for further studies of the biology and therapy of human signet ring cell (or Borrmann's type IV carcinoma) gastric carcinoma.


Gaps in Addressing Cardiovascular Risk in Rheumatoid Arthritis: Assessing Performance Using Cardiovascular Quality Indicators.
Cardiovascular disease (CVD) is a major comorbidity for patients with rheumatoid arthritis (RA). This study sought to determine the performance of 11 recently developed CVD quality indicators (QI) for RA in clinical practice. Medical charts for patients with RA (early disease or biologic-treated) followed at 1 center were retrospectively reviewed. A systematic assessment of adherence to 11 QI over a 2-year period was completed. Performance on the QI was reported as a percentage pass rate. There were 170 charts reviewed (107 early disease and 63 biologic-treated). The most frequent CVD risk factors present at diagnosis (early disease) and biologic start (biologic-treated) included hypertension (26%), obesity (25%), smoking (21%), and dyslipidemia (15%). Performance on the CVD QI was highly variable. Areas of low performance (< 10% pass rates) included documentation of a formal CVD risk assessment, communication to the primary care physician (PCP) that patients with RA were at increased risk of CVD, body mass index documentation and counseling if overweight, communication to a PCP about an elevated blood pressure, and discussion of risks and benefits of antiinflammatories in patients at CVD risk. Rates of diabetes screening and lipid screening were 67% and 69%, respectively. The area of highest performance was observed for documentation of intent to taper corticosteroids (98%-100% for yrs 1 and 2, respectively). Gaps in CVD risk management were found and highlight the need for quality improvements. Key targets for improvement include coordination of CVD care between rheumatology and primary care, and communication of increased CVD risk in RA.


GARD, a new way to battle with chronic respiratory diseases, from disease oriented programmes to global partnership.
Initiated by World Health Organization (WHO) Global Chronic Respiratory Disease (CRD)-oriented programmes, Global Initiative on Asthma (GINA), GOLD-Global Initiative for Chronic Obstructive Pulmonary Disease (COPD), Allergic Rhinitis and its Impact on Asthma (ARIA), and Practical Approach to Lung Health (PAL) have catalyzed creation of the Global Alliance Against CRD (GARD). Forty-five countries sharing GARD's goal to reduce the burden of CRD joint GARD. In 20 countries with reliable death estimates, CRD mortality has been analyzed in 2000, 2005, 2010 and 2015. Dramatic decline in CRD mortality is seen in Kyrgyzstan, Netherlands, Italy and Republic of Korea (69%, 55%, 48%, and 48%). Positive trend in COPD mortality is seen for Lithuania (36% decline) and Spain (21%). In France, Japan, Mexico, Romania and Costa Rica, positive trend for asthma mortality is obvious from 2000 to 2015 from about 40% in France and Romania, 50% and Mexico and Czech Republic, 65% in Japan and 69% in Belgium. In Costa Rica zero asthma mortality was registered in 2015. In Czechia and Belgium decline is seen from 2000 to 2005, which then stabilized in Czech Republic and went further down in Belgium. In Finland initially, low asthma mortality remains practically unchanged with slight decline in 2015. In other countries analyzed, we did not see any positive trend in CRD mortality. In all countries with positive CRD dynamic WHO introduced activities remained active, they have been taken into local guidelines and practice and supported national authorities in implementing these evidence-based guidelines. Before GARD launch WHO initiated activities produced a good basis for further GARD movement and by 2010 we see a visible positive trend in CRD mortality in success countries. By 2015 when WHO noncommunicable disease (NCD) Global Action Plan 2013-2020 rollouts globally dramatic decline in total CRD mortality and particularly in Asthma and COPD mortality became obvious. Global disease oriented programmes, national and international partnerships combined with the Global NCD Action Plan most probable produce a positive synergistic effect on the mortality from CRD.


Matrix Metalloproteinase-2 Knockout and Heterozygote Mice Are Protected from Hydronephrosis and Kidney Fibrosis after Unilateral Ureteral Obstruction.
Matrix Metalloproteinase-2 (Mmp2) is a collagenase known to be important in the development of renal fibrosis. In unilateral ureteral obstruction (UUO) the obstructed kidney (OK) develops fibrosis, while the contralateral (CL) does not. In this study we investigated the effect of UUO on gene expression, fibrosis and pelvic remodeling in the kidneys of Mmp2 deficient mice (Mmp2-/-), heterozygous animals (Mmp2+/-) and wild-type mice (Mmp2+/+). Sham operated animals served as controls (Cntrl). UUO was prepared under isoflurane anaesthesia, and the animals were sacrificed after one week. UUO caused hydronephrosis, dilation of renal tubules, loss of parenchymal thickness, and fibrosis. Damage was most severe in Mmp2+/+ mice, while both Mmp2-/- and Mmp2+/- groups showed considerably milder hydronephrosis, no tubular necrosis, and less tubular dilation. Picrosirius red quantification of fibrous collagen showed 1.63±0.25% positivity in OK and 0.29±0.11% in CL (p<0.05) of Mmp2+/+, Mmp2-/- OK and Mmp2-/- CL exhibited only 0.49±0.09% and 0.23±0.04% (p<0.05) positivity, respectively. Mmp2+/- OK and Mmp2+/- CL showed 0.43±0.09% and 0.22±0.06% (p<0.05) positivity, respectively. Transcriptomic analysis showed that 26 genes (out of 48 examined) were differentially expressed by ANOVA (p<0.05). 25 genes were upregulated in Mmp2+/+ OK compared to Mmp2+/+ CL: Adamts1, -2, Col1a1, -2, -3a1, -4a1, -5a1, -5a2, Dcn, Fbln1, -5, Fmod, Fn1, Itga2, Loxl1, Mgp, Mmp2, -3, Nid1, Pdgfb, Spp1, Tgfb1, Timp2, Trf, Vim. In Mmp2-/- and Mmp2+/- 18 and 12 genes were expressed differentially between OK and CL, respectively. Only Mmp2 was differentially regulated when comparing Mmp2-/- OK and Mmp2+/- OK. Under stress, it appears that Mmp2+/- OK responds with less Mmp2 upregulation than Mmp2+/+ OK, suggesting that there is a threshold level of Mmp2 necessary for damage and fibrosis to occur. In conclusion, reduced Mmp2 expression during UUO protects mice against hydronephrosis and renal fibrosis.


Acute B lymphoblastic leukaemia-propagating cells are present at high frequency in diverse lymphoblast populations.
Leukaemia-propagating cells are more frequent in high-risk acute B lymphoblastic leukaemia than in many malignancies that follow a hierarchical cancer stem cell model. It is unclear whether this characteristic can be more universally applied to patients from non-'high-risk' sub-groups and across a broad range of cellular immunophenotypes. Here, we demonstrate in a wide range of primary patient samples and patient samples previously passaged through mice that leukaemia-propagating cells are found in all populations defined by high or low expression of the lymphoid differentiation markers CD10, CD20 or CD34. The frequency of leukaemia-propagating cells and their engraftment kinetics do not differ between these populations. Transcriptomic analysis of CD34(high) and CD34(low) blasts establishes their difference and their similarity to comparable normal progenitors at different stages of B-cell development. However, consistent with the functional similarity of these populations, expression signatures characteristic of leukaemia propagating cells in acute myeloid leukaemia fail to distinguish between the different populations. Together, these findings suggest that there is no stem cell hierarchy in acute B lymphoblastic leukaemia.


A multilevel analysis on the relationship between neighbourhood poverty and public hospital utilization: is the high Indigenous morbidity avoidable?
The estimated life expectancy at birth for Indigenous Australians is 10-11 years less than the general Australian population. The mean family income for Indigenous people is also significantly lower than for non-Indigenous people. In this paper we examine poverty or socioeconomic disadvantage as an explanation for the Indigenous health gap in hospital morbidity in Australia. We utilised a cross-sectional and ecological design using the Northern Territory public hospitalisation data from 1 July 2004 to 30 June 2008 and socio-economic indexes for areas (SEIFA) from the 2006 census. Multilevel logistic regression models were used to estimate odds ratios and confidence intervals. Both total and potentially avoidable hospitalisations were investigated. This study indicated that lifting SEIFA scores for family income and education/occupation by two quintile categories for low socio-economic Indigenous groups was sufficient to overcome the excess hospital utilisation among the Indigenous population compared with the non-Indigenous population. The results support a reframing of the Indigenous health gap as being a consequence of poverty and not simplistically of ethnicity. Socio-economic disadvantage is a likely explanation for a substantial proportion of the hospital morbidity gap between Indigenous and non-Indigenous populations. Efforts to improve Indigenous health outcomes should recognise poverty as an underlying determinant of the health gap.


Assessment of flame retardants in river water using a ceramic dosimeter passive sampler.
Novel brominated (BFRs) and organophosphorus (OPFRs) flame retardants were monitored in river water using the ceramic dosimeter passive sampling device with HLB (hydrophilic-lipophilic balance) as sorbent. Laboratory calibrations were performed to determine sampling rates for each compound using the Archie's law exponent. The passive sampling device was used to determine the presence of 6 BFRs in the River Aire (United Kingdom), selected according to their ubiquitous presence in the River Aire. Passive sampling integrated river water concentrations ranged from 0.010 to 5.6 μg L(-1) for all OPFRs, while BFRs were not detected with this specific passive sampler configuration. Decreased sampling rates were evidenced after 3 weeks of deployment, probably due to fouling. Good agreement between integrated and snapshot water concentrations was obtained, indicating the efficiency of the passive sampler for the monitoring of OPFRs in river water.


Dysthyroid Orbitopathy Presenting with Gaze-Evoked Amaurosis: Case Report and Review of the Literature.
Gaze-evoked amaurosis (GEA) describes visual loss associated with eccentric gaze that recovers when the eye is returned to primary position. Here we describe an unusual case of bilateral GEA as the presenting feature of dysthyroid orbitopathy. This is only the third such case to be reported in the literature and the first to feature bilateral GEA in all positions of gaze without accompanying proptosis or ophthalmoplegia. A 50-year-old man who had recently commenced treatment for thyrotoxicosis presented with a 3-week history of typical GEA in both eyes in all positions of gaze. He subsequently developed a bilateral compressive optic neuropathy which was only partially responsive to high dose steroid therapy. Although an uncommon presenting feature of dysthyroid orbitopathy, GEA is an ominous symptom that may precede sight-threatening optic nerve compromise. When present, early immunosuppressive and/or decompressive treatment should be considered.


Leukemic marrow infiltration reveals a novel role for Egr3 as a potent inhibitor of normal hematopoietic stem cell proliferation.
Cytopenias resulting from the impaired generation of normal blood cells from hematopoietic precursors are important contributors to morbidity and mortality in patients with leukemia. However, the process by which normal hematopoietic cells are overtaken by emerging leukemia cells and how different subsets of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) are distinctly influenced during leukemic cell infiltration is poorly understood. To investigate these important questions, we used a robust nonirradiated mouse model of human MLL-AF9 leukemia to examine the suppression of HSCs and HPCs during leukemia cell expansion in vivo. Among all the hematopoietic subsets, long-term repopulating HSCs were the least reduced, whereas megakaryocytic-erythroid progenitors were the most significantly suppressed. Notably, nearly all of the HSCs were forced into a noncycling state in leukemic marrow at late stages, but their reconstitution potential appeared to be intact upon transplantation into nonleukemic hosts. Gene expression profiling and further functional validation revealed that Egr3 was a strong limiting factor for the proliferative potential of HSCs. Therefore, this study provides not only a molecular basis for the more tightened quiescence of HSCs in leukemia, but also a novel approach for defining functional regulators of HSCs in disease.


Multiple siderophores: bug or feature?
It is common for bacteria to produce chemically diverse sets of small Fe-binding molecules called siderophores. Studies of siderophore bioinorganic chemistry have firmly established the role of these molecules in Fe uptake and provided great insight into Fe complexation. However, we still do not fully understand why microbes make so many siderophores. In many cases, the release of small structural variants or siderophore fragments has been ignored, or considered as an inefficiency of siderophore biosynthesis. Yet, in natural settings, microbes live in complex consortia and it has become increasingly clear that the secondary metabolite repertoires of microbes reflect this dynamic environment. Multiple siderophore production may, therefore, provide a window into microbial life in the wild. This minireview focuses on three biochemical routes by which multiple siderophores can be released by the same organism-multiple biosynthetic gene clusters, fragment release, and precursor-directed biosynthesis-and highlights emergent themes related to each. We also emphasize the plurality of reasons for multiple siderophore production, which include enhanced iron uptake via synergistic siderophore use, microbial warfare and cooperation, and non-classical functions such as the use of siderophores to take up metals other than Fe.


High-power widely tunable Tm:fibre lasers pumped by an Er,Yb co-doped fibre laser at 1.6 mum.
High-power and widely tunable Tm-doped silica fibre lasers cladding-pumped and core-pumped by a 1565 nm Er,Yb fibre laser are reported. Output power up to 19.2W was generated from the cladding-pumped cavity configuration for ~38.2W of launched pump power and with slope efficiency up to ~72% with respect to absorbed pump power. Wavelength tuning was realized by use of an external cavity containing a diffraction grating. A maximum output power of 17.4 W at 1941 nm was generated for 38.2 W of launched pump power and the operating wavelength could be tuned over 202 nm from 1859 to 2061 nm. In the core-pumped configuration, a maximum output power of 12.1 W was generated at 1851 nm for 23.1 W absorbed pump power using a simple free-running cavity configuration with only ~24 cm of Tm-doped fibre. By employing a tunable cavity configuration, the operating wavelength of the core-pumped Tm:fibre laser could be tuned over 250 nm from 1723-1973 nm at multiwatt power levels.


Recent results of medium wave infrared compressive sensing.
The application of compressive sensing (CS) for imaging has been extensively investigated and the underlying mathematical principles are well understood. The theory of CS is motivated by the sparse nature of real-world signals and images, and provides a framework in which high-resolution information can be recovered from low-resolution measurements. This, in turn, enables hardware concepts that require much fewer detectors than a conventional sensor. For infrared imagers there is a significant potential impact on the cost and footprint of the sensor. When smaller focal plane arrays (FPAs) to obtain large images are allowed, large formats FPAs are unnecessary. From a hardware standpoint, this benefit is independent of the actual level of compression and effective data rate reduction, which depend on the choice of codes and information recovery algorithm. Toward this end, we used a CS testbed for mid-wave infrared (MWIR) to experimentally show that information at high spatial resolution can be successfully recovered from measurements made with a small FPA. We describe the highly parallel and scalable CS architecture of the testbed, and its implementation using a reflective spatial light modulator and a focal plane array with variable pixel sizes. We also discuss the impact of real-world devices and the effect of sensor calibration that must be addressed in practice. Finally, we present preliminary results of image reconstruction, which demonstrate the testbed operation. These results experimentally confirm that high-resolution spatial information (for tasks such as imaging and target detection) can be successfully recovered from low-resolution measurements. We also discuss the potential system-level benefits of CS for infrared imaging, and some of the challenges that must be addressed in future infrared CS imagers designs.


Synthesis and cytotoxic evaluation of some novel quinoxalinedione diarylamide sorafenib analogues.
A series of novel sorafenib analogues containing a quinoxalinedione ring and amide linker were synthesized. A total of 9 novel compounds in 6 synthetic steps were synthesized. Briefly, the amino group of p-aminophenol was first protected which then followed by O-arylation with 5-chloro-2-nitroaniline to provide compound d. Reduction of the nitro group of compound d and cyclization of the diamine group of compound e with oxalic acid afforded compound f which on deacetylation yeilded compound g. Then compound g was reacted with different acyl halides to afford the target compounds 1h-1p. Chemical structures of synthesized compounds were confirmed by 1H NMR and FT-IR analysis. All compounds were evaluated at 1, 10, 50 and 100 μM concentrations for their cytotoxicity against HeLa and MCF-7 cancer cell lines. Some of the compounds showed good cytotoxic activity, especially compounds 1i and 1k-1n with the IC50 values of 19, 16, 22, 18, and 16 μM against MCF-7 cell line and 20, 18, 25, 20, and 18 μM against HeLa cell line, respectively.


Longitudinal incidence and prevalence of adverse outcomes of diabetes mellitus in elderly patients.
The natural history of type 2 diabetes mellitus (DM) in the elderly has not been previously described in a national longitudinal sample. This national longitudinal analysis (January 1, 1991, to December 31, 2004) examines mortality and morbidity rates in a representative sample of elderly patients newly diagnosed as having DM. Medicare beneficiaries diagnosed as having DM in 1994 (n=33,772) were compared with a control group (n=25,563) regarding death, lower extremity complications, nephropathy, retinopathy, cardiovascular complications, and cerebrovascular complications. The DM group had excess mortality of 9.2% by year 11 compared with the control group. By 2004, 91.8% of the DM group experienced an adverse complication compared with 72.0% of the control group. The DM group had a higher prevalence and incidence of microvascular and macrovascular complications at all time points compared with controls. Patients with DM were at increased risk for all lower extremity complications, particularly those requiring surgical intervention (gangrene, debridement, and amputation). Cardiovascular complications were a leading cause of morbidity, with 57.6% of the DM group diagnosed as having heart failure compared with 34.1% of the controls. Elderly persons newly diagnosed as having DM experienced high rates of complications during 10-year follow-up, far in excess of elderly persons without this diagnosis, implying a substantial burden on the individual and on the health care system.


Much ado about grit: A meta-analytic synthesis of the grit literature.
Grit has been presented as a higher order personality trait that is highly predictive of both success and performance and distinct from other traits such as conscientiousness. This paper provides a meta-analytic review of the grit literature with a particular focus on the structure of grit and the relation between grit and performance, retention, conscientiousness, cognitive ability, and demographic variables. Our results based on 584 effect sizes from 88 independent samples representing 66,807 individuals indicate that the higher order structure of grit is not confirmed, that grit is only moderately correlated with performance and retention, and that grit is very strongly correlated with conscientiousness. We also find that the perseverance of effort facet has significantly stronger criterion validities than the consistency of interest facet and that perseverance of effort explains variance in academic performance even after controlling for conscientiousness. In aggregate our results suggest that interventions designed to enhance grit may only have weak effects on performance and success, that the construct validity of grit is in question, and that the primary utility of the grit construct may lie in the perseverance facet. (PsycINFO Database Record


Theoretical aspects of dynamic nuclear polarization in the solid state--spin temperature and thermal mixing.
Dynamic nuclear polarization is a method which allows for a dramatic increase of the NMR signals due to polarization transfer between electrons and their neighboring nuclei, via microwave irradiation. These experiments have become popular in recent years due to the ability to create hyper-polarized chemically and biologically relevant molecules, in frozen glass forming mixtures containing free radicals. Three mechanisms have been proposed for the polarization transfer between electrons and their surrounding nuclei in such non-conducting samples: the solid effect and cross effect mechanisms, which are based on quantum mechanics and relaxation on small spin systems, and thermal mixing, which originates from the thermodynamic macroscopic notion of spin temperature. We have recently introduced a spin model, which is based on the density matrix formalism and includes relaxation, and applied it to study the solid effect and cross effect mechanisms on small spin systems. In this publication we use the same model to describe the thermal mixing mechanism, and the creation of spin temperature. This is obtained without relying on the spin temperature formalism. Simulations of small model systems are used on systems with homogeneously and inhomogeneously broadened EPR lines. For the case of a homogeneously broadened line we show that the nuclear enhancement results from the thermal mixing and solid effect mechanisms, and that spin temperatures are created in the system. In the inhomogeneous case the enhancements are attributed to the solid effect and cross effect mechanisms, but not thermal mixing.


Plasmodium falciparum clearance in clinical studies of artesunate-amodiaquine and comparator treatments in sub-Saharan Africa, 1999-2009.
Artemisinin-based combination therapy (ACT) is the recommended first-line therapy for uncomplicated Plasmodium falciparum malaria worldwide but decreased artemisinin susceptibility, phenotypically characterized as slow parasite clearance time (PCT), has now been reported in Southeast Asia. This makes it all too important to measure the dynamics of parasite clearance in African patients treated with ACT over time, to understand trends and detect changes early enough to intervene Individual patient data from 27 clinical trials of artesunate-amodiaquine (ASAQ) vs comparators conducted between 1999 and 2009 were analysed for parasite clearance on modified intent-to-treat (ITT) basis. Overall 15,017 patients treated for uncomplicated P. falciparum malaria at 44 sites in 20 sub-Saharan African countries were included in the analysis; 51% (n=7,660) vs 49% (n=7,357) were treated with ASAQ and comparator treatments, respectively. Seventy-seven per cent (77%) were children under six years of age. The proportion of the patients treated with ASAQ with persistent parasitaemia on Day 2 was 8.6%, and 1.5% on Day 3. Risk factor for not clearing parasites on Day 2 and Day 3 calculated by multivariate logistic regression with random effect on site and controlling for treatment were: high parasitaemia before treatment was (adjusted risk ratios (AOR) 2.12, 95% CI 1.91-2.35, AOR 2.43, 95% CI 1.98-3.00, respectively); non-ACT treatment (p=0.001, for all comparisons). Anaemia (p=0.001) was an additional factor for Day 2 and young age (p=0.005) for Day 3.In patients treated with ASAQ in studies who had complete parasitaemia data every 24 hours up to Day 3 and additionally Day 7, the parasite reduction ratio was 93.9% by Day 1 and 99.9% by Day 2. Using the median parasitaemia before treatment (p0=27,125 μL) and a fitted model, the predicted PCT (pPCT = 3.614*ln (p0) - 6.135, r(2) = 0.94) in ASAQ recipients was 31 hours. Within the period covered by these studies, rapid Plasmodium falciparum clearance continues to be achieved in Sub-Saharan African patients treated with ACT, and in particular with ASAQ. The prediction formula for parasite clearance time could be a pragmatic tool for studies with binary outcomes and once-daily sampling, both for research and monitoring purposes.


Combining findings from gaze and electroencephalography recordings to study timing in a visual tracking task.
Electroencephalography (EEG) and gaze data have traditionally been separated in neurocognitive studies because of the artefacts that even small controlled eye movements produce. Study of gaze control in a visual tracking task provides information about an individual's prospective control. By including gaze events in the EEG analysis, we studied prospective control and its neural correlates during deceleration in a visual tracking task. Adult participants followed with their gaze a small car moving horizontally on a large screen, where the final approach of the car was temporarily occluded, and pushed a button to stop the car at the reappearance point. Two gaze events, the behavioural push button response and the nonbehavioural stimulus onset, were used to time-lock the averaged event-related potential (ERP) waveform. A significant effect of deceleration on peak amplitude in parietal channel Pz (P<0.05) was found when ERP waveforms were time-locked to the prospective gaze shift over the occluder. The peak decreased in amplitude as car deceleration increased when participants successfully stopped the car, indicating successful deceleration discrimination. No such effect was found when ERP waveforms were time-locked to any of the other events. Thus, a traditional stimulus onset time-locking procedure is likely to distort the averaged signal and consequently hide important Pz-peak amplitude differences on the prospective timing of decelerating object motion during occlusion. This study shows the importance of including behavioural data when studying neural correlates of prospective control and proposes active incorporation of behavioural data into the EEG analysis.


A first attempt to numerically compute forces on birds in V formation.
A model for studying the flow forces experienced by cylinders placed in V formation is presented, and an elementary comparison with flocking birds is made. The cylinders are modeled as two-dimensional square bodies exposed to incoming flow at Reynolds number 100. The effects of angle of formation (alpha), streamwise spacing (S(s)), and number of cylinders (N) on parameters such as the coefficient of drag, coefficient of lateral force, and Strouhal number are studied. It is observed that the drag experienced by the cylinders decreases with a decrease in the angle of formation. The leading cylinder experiences the smallest drag, irrespective of the angle. The drag becomes less than the drag on an isolated cylinder at certain angles depending on the position of the cylinder in the formation. The average drag on cylinders in V formation is found to be less than on an isolated cylinder, leading to energy saving when flying in formation. It is also noted that the cylinders experience a substantial lateral force. Study of this simple model may help better understand certain features of flocking birds.


Fibroblast growth factor 19 expression correlates with tumor progression and poorer prognosis of hepatocellular carcinoma.
Although fibroblast growth factor 19 (FGF19) can promote liver carcinogenesis in mice, its involvement in human hepatocellular carcinoma (HCC) has not been well investigated. FGF19, a member of the FGF family, has unique specificity for its receptor FGFR4. This study aimed to clarify the involvement of FGF19 in the development of HCC. We investigated human FGF19 and FGFR4 expression in 40 hepatocellular carcinoma specimens using quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) analysis and immunohistochemistry. Moreover, we examined the expression and the distribution of FGF19 and FGFR4 in 5 hepatocellular carcinoma cell lines (HepG2, HuH7, HLE, HLF, and JHH7) using RT-PCR and immunohistochemistry. To test the role of the FGF19/FGFR4 system in tumor progression, we used recombinant FGF19 protein and small interfering RNA (siRNA) of FGF19 and FGFR4 to regulate their concentrations. We found that FGF19 was significantly overexpressed in HCCs as compared with corresponding noncancerous liver tissue (P < 0.05). Univariate and multivariate analyses revealed that the tumor FGF19 mRNA expression was an independent prognostic factor for overall and disease-free survival. Moreover, we found that the FGF19 recombinant protein could increase the proliferation (P < 0.01, n = 12) and invasion (P < 0.01, n = 6) capabilities of human hepatocellular carcinoma cell lines and inhibited their apoptosis (P < 0.01, n = 12). Inversely, decreasing FGF19 and FGFR4 expression by siRNA significantly inhibited proliferation and increased apoptosis in JHH7 cells (P < 0.01, n = 12). The postoperative serum FGF19 levels in HCC patients was significantly lower than the preoperative levels (P < 0.01, n = 29). FGF19 is critically involved in the development of HCCs. Targeting FGF19 inhibition is an attractive potential therapeutic strategy for HCC.


Human induced pluripotent stem cell-derived versus adult cardiomyocytes: an in silico electrophysiological study on effects of ionic current block.
Two new technologies are likely to revolutionize cardiac safety and drug development: in vitro experiments on human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and in silico human adult ventricular cardiomyocyte (hAdultV-CM) models. Their combination was recently proposed as a potential replacement for the present hERG-based QT study for pharmacological safety assessments. Here, we systematically compared in silico the effects of selective ionic current block on hiPSC-CM and hAdultV-CM action potentials (APs), to identify similarities/differences and to illustrate the potential of computational models as supportive tools for evaluating new in vitro technologies. In silico AP models of ventricular-like and atrial-like hiPSC-CMs and hAdultV-CM were used to simulate the main effects of four degrees of block of the main cardiac transmembrane currents. Qualitatively, hiPSC-CM and hAdultV-CM APs showed similar responses to current block, consistent with results from experiments. However, quantitatively, hiPSC-CMs were more sensitive to block of (i) L-type Ca(2+) currents due to the overexpression of the Na(+) /Ca(2+) exchanger (leading to shorter APs) and (ii) the inward rectifier K(+) current due to reduced repolarization reserve (inducing diastolic potential depolarization and repolarization failure). In silico hiPSC-CMs and hAdultV-CMs exhibit a similar response to selective current blocks. However, overall hiPSC-CMs show greater sensitivity to block, which may facilitate in vitro identification of drug-induced effects. Extrapolation of drug effects from hiPSC-CM to hAdultV-CM and pro-arrhythmic risk assessment can be facilitated by in silico predictions using biophysically-based computational models.


Comparison of DNA extraction methods for microbial community profiling with an application to pediatric bronchoalveolar lavage samples.
Barcoded amplicon sequencing is rapidly becoming a standard method for profiling microbial communities, including the human respiratory microbiome. While this approach has less bias than standard cultivation, several steps can introduce variation including the type of DNA extraction method used. Here we assessed five different extraction methods on pediatric bronchoalveolar lavage (BAL) samples and a mock community comprised of nine bacterial genera to determine method reproducibility and detection limits for these typically low complexity communities. Additionally, using the mock community, we were able to evaluate contamination and select a relative abundance cut-off threshold based on the geometric distribution that optimizes the trade off between detecting bona fide operational taxonomic units and filtering out spurious ones. Using this threshold, the majority of genera in the mock community were predictably detected by all extraction methods including the hard-to-lyse Gram-positive genus Staphylococcus. Differences between extraction methods were significantly greater than between technical replicates for both the mock community and BAL samples emphasizing the importance of using a standardized methodology for microbiome studies. However, regardless of method used, individual patients retained unique diagnostic profiles. Furthermore, despite being stored as raw frozen samples for over five years, community profiles from BAL samples were consistent with historical culturing results. The culture-independent profiling of these samples also identified a number of anaerobic genera that are gaining acceptance as being part of the respiratory microbiome. This study should help guide researchers to formulate sampling, extraction and analysis strategies for respiratory and other human microbiome samples.


Surface chemical-modification for engineering the intrinsic physical properties of inorganic two-dimensional nanomaterials.
Two-dimensional (2D) nanomaterials, especially the inorganic ultrathin nanosheets with single or few-atomic layers, have been extensively studied due to their special structures and rich physical properties coming from the quantum confinement of electrons. With atomic-scale thickness, 2D nanomaterials have an extremely high specific surface area enabling their surface phase to be as important as bulk counterparts, and therefore provide an alternative way of modifying the surface phase for engineering the intrinsic physical properties of inorganic 2D nanomaterials. In this review, we focus on recent research concerning surface chemical modification strategies to effectively engineer the intrinsic physical properties of inorganic 2D nanomaterials. We highlight the newly developed regulation strategies of surface incorporation, defect engineering, and structure modulation of inorganic 2D nanomaterials, which respectively influence the intrinsic conductivity, band structure, and magnetism while maintaining the primary 2D freestanding structures that are vital for 2D based ultrasensitive electronic response, enhanced catalytic and magnetocaloric capabilities.


Endophthalmitis Prophylaxis in Cataract Surgery: Overview of Current Practice Patterns Around the World.
Acute-onset postoperative endophthalmitis after cataract surgery remains a rare but important cause of visual loss. There is no global consensus regarding the optimal strategies for prophylaxis of endophthalmitis and practices vary substantially around the world, especially with respect to the use of intracameral antibiotics. The European Society of Cataract & Refractive Surgeons in a randomized clinical trial (2007) reported an approximately 5-fold reduction in endophthalmitis rates associated with the use of intracameral cefuroxime. Despite this report, the use of intracameral antibiotics has not been universally adopted. Various endophthalmitis prophylaxis patterns around the world (including the United States, Canada, Australia/New Zealand, Japan, China, India, Indonesia, South Africa, Argentina, Russia, Sweden and Mexico) are compared. Each contributing author was asked to provide similar information, including endophthalmitis rates based on published studies, current practice patterns, and in some cases original survey data. Various methods were used to obtain this information, including literature reviews, expert commentary, and some new survey data not previously published. Many different practice patterns were reported from around the world, specifically with respect to the use of intracameral antibiotics. There is no worldwide consensus regarding endophthalmitis prophylaxis with cataract surgery.