Methods for evaluating delivery systems for scaling-up malaria control intervention.
Despite increased resources over the past few years the coverage of malaria control interventions is still inadequate to reach national and international targets and achieve the full potential of the interventions to improve population health. One of the reasons for this inadequate coverage of efficacious interventions is the limited understanding of the optimum delivery systems of the interventions in different contexts. Although there have been debates about how to deliver interventions, the methods for evaluating the effectiveness of different delivery systems have rarely been discussed. Delivery of interventions is relatively complex and a thorough evaluation would need to look holistically at multiple steps in the delivery process and at multiple factors influencing the process. A better understanding of the strength of the evidence on delivery system effectiveness is needed in order to optimise delivery of efficacious interventions. A literature review was conducted of methods used to evaluate delivery systems for insecticide treated nets, intermittent preventive treatment in pregnant women, and treatment for malaria in children. The methodology of delivery system evaluations varied. There were inconsistencies between objectives and methods of the evaluations including inappropriate outcome measures and unnecessary controls. There were few examples where the delivery processes were adequately described, or measured. We propose a cross sectional observational study design with attribution of the outcomes to a specific delivery system as an appropriate method for evaluating delivery systems at scale. The proposed evaluation framework is adaptable to natural experiments at scale, and can be applied using data from routine surveys such as the Demographic and Health Surveys, modified by the addition of one to two questions for each intervention. This framework has the potential to enable wider application of rigorous evaluations and thereby improve the evidence base on which decisions about delivery systems for malaria control and other public health interventions are taken.


Accounting for differences in the bioactivity and bioavailability of vitamers.
Essentially all vitamins exist with multiple nutritionally active chemical species often called vitamers. Our quantitative understanding of the bioactivity and bioavailability of the various members of each vitamin family has increased markedly, but many issues remain to be resolved concerning the reporting and use of analytical data. Modern methods of vitamin analysis rely heavily on chromatographic techniques that generally allow the measurement of the individual chemical forms of vitamins. Typical applications of food analysis include the evaluation of shelf life and storage stability, monitoring of nutrient retention during food processing, developing food composition databases and data needed for food labeling, assessing dietary adequacy and evaluating epidemiological relationships between diet and disease. Although the usage of analytical data varies depending on the situation, important issues regarding how best to present and interpret the data in light of the presence of multiple vitamers are common to all aspects of food analysis. In this review, we will evaluate the existence of vitamers that exhibit differences in bioactivity or bioavailability, consider when there is a need to address differences in bioactivity or bioavailability of vitamers, and then consider alternative approaches and possible ways to improve the reporting of data. Major examples are taken from literature and experience with vitamin B(6) and folate.


Disparities in testing for renal function in UK primary care: cross-sectional study.
In the UK, explicit quality standards for chronic disease management, including for diabetes and chronic kidney disease (CKD), are set out National Service Frameworks and pay-for-performance indicators. These conditions are common with a prevalence of 4% and 5.4%, respectively. CKD is largely asymptomatic, detected following renal function testing and important because associated with increased mortality and morbidity, especially in people with diabetes and proteinuria. To investigate who has their renal function tested and any association with age, sex, ethnicity and diabetes. A cross-sectional survey in a primary care research network in south-west London (n = 220 721). The following data were extracted from routine data: age, gender, ethnicity, latest serum creatinine, diagnosis of diabetes and recording of proteinuria. We used logistic regression to explore any association in testing for CKD. People (82.1%) with diabetes had renal function and proteinuria tested; the proportion was much smaller (<0.5%) in those without. Women were more likely to have a creatinine test than men (28% versus 24%, P < 0.05), but this association was modified by age, ethnicity and presence of diabetes. People >75 years and with diabetes were most likely to have been tested. Black [adjusted odds ratio (AOR) 2.1, 95% confidence interval (CI) 2.0-2.2] and south Asian (AOR 1.65, 95% CI 1.56-1.75) patients were more likely to be tested than whites. Those where ethnicity was not stated were the only group not tested more than whites. Quality improvement initiatives and equity audits, which include CKD should take account of disparities in renal function testing.


STED nanoscopy: a glimpse into the future.
The well-known saying of "Seeing is believing" became even more apt in biology when stimulated emission depletion (STED) nanoscopy was introduced in 1994 by the Nobel laureate S. Hell and coworkers. We presently stand at a juncture. Nanoscopy represented a revolution in fluorescence microscopy but now is a mature technique applied to many branches of biology, physics, chemistry, and materials science. We are currently looking ahead to the next generation of optical nanoscopes, to the new key player that will arise in the forthcoming years. This article gives an overview of the various cutting-edge implementations of STED nanoscopy and tries to shine a light into the future: imaging everything faster with unprecedented sensitivity and label-free.


Metformin and prostate cancer stem cells: a novel therapeutic target.
Prostate cancer is the second most frequently diagnosed cancer in the world. Localized disease can be effectively treated with radiation therapy or radical prostatectomy. However, advanced prostate cancer is more difficult to treat and if metastatic, is incurable. There is a need for more effective therapy for advanced prostate cancer. One potential target is the cancer stem cell (CSC). CSCs have been described in several solid tumors, including prostate cancer, and contribute to therapeutic resistance and tumor recurrence. Metformin, a common oral biguanide used to treat type 2 diabetes, has been demonstrated to have anti-neoplastic effects. Specifically, metformin targets CSCs in breast cancer, pancreatic cancer, glioblastoma and colon cancer. Metformin acts directly on the mitochondria to inhibit oxidative phosphorylation and reduce mitochondrial ATP production. This forces tumor cells to compensate by increasing the rate of glycolysis. CSCs rely heavily on mitochondrial oxidative phosphorylation for energy production. The glycolytic switch results in an energy crisis in these cells. Metformin could be used to exploit this metabolic weakness in CSCs. This would increase CSC sensitivity to conventional cancer therapies, circumventing treatment resistance and enhancing treatment efficacy. This review will explore the characteristics of prostate CSCs, their role in tumor propagation and therapeutic resistance and the role of metformin as a potential prostate CSC sensitizer to current anticancer therapies.


Global gene expression profiling related to temperature-sensitive growth abnormalities in interspecific crosses between tetraploid wheat and Aegilops tauschii.
Triploid wheat hybrids between tetraploid wheat and Aegilops tauschii sometimes show abnormal growth phenotypes, and the growth abnormalities inhibit generation of wheat synthetic hexaploids. In type II necrosis, one of the growth abnormalities, necrotic cell death accompanied by marked growth repression occurs only under low temperature conditions. At normal temperature, the type II necrosis lines show grass-clump dwarfism with no necrotic symptoms, excess tillers, severe dwarfism and delayed flowering. Here, we report comparative expression analyses to elucidate the molecular mechanisms of the temperature-dependent phenotypic plasticity in the triploid wheat hybrids. We compared gene and small RNA expression profiles in crown tissues to characterize the temperature-dependent phenotypic plasticity. No up-regulation of defense-related genes was observed under the normal temperature, and down-regulation of wheat APETALA1-like MADS-box genes, considered to act as flowering promoters, was found in the grass-clump dwarf lines. Some microRNAs, including miR156, were up-regulated, whereas the levels of transcripts of the miR156 target genes SPLs, known to inhibit tiller and branch number, were reduced in crown tissues of the grass-clump dwarf lines at the normal temperature. Unusual expression of the miR156/SPLs module could explain the grass-clump dwarf phenotype. Dramatic alteration of gene expression profiles, including miRNA levels, in crown tissues is associated with the temperature-dependent phenotypic plasticity in type II necrosis/grass-clump dwarf wheat hybrids.


Consumptive coagulopathy is associated with a disturbed host response in patients with sepsis.
A prolonged prothrombin time (PT) is a common feature in sepsis indicating consumptive coagulopathy. To determine the association between a prolonged PT and aberrations in other host response mechanisms in sepsis. Patients admitted to the intensive care unit with sepsis were divided in quartiles according to the highest PT value measured within 24 h after admission. The host response was evaluated by measuring 19 plasma biomarkers reflecting pathways implicated in sepsis pathogenesis and by blood leukocyte gene expression profiling. Of 1524 admissions for sepsis, 386 (25.3%) involved patients with a normal PT (≤12.7 s); the remaining quartiles entailed 379 (24.9%) patients with a slightly prolonged PT (12.8 ≤ PT ≤ 15.0 s), 383 (25.1%) with an intermediately prolonged PT (15.1 ≤ PT ≤ 17.2 s), and 376 (24.7%) with an extremely prolonged PT (≥17.3 s). While patients with an extremely prolonged PT showed an increased crude mortality up to 1 year after admission, none of the prolonged PT groups was independently associated with 30-day adjusted mortality. Comparison of the host response between patients with a normal PT or an extremely prolonged PT matched for baseline characteristics including severity of disease showed that an extremely prolonged PT was associated with impaired anticoagulant mechanisms, a more disturbed endothelial barrier integrity and increased systemic inflammation, and blood leukocyte transcriptomes indicating more prominent metabolic reprogramming and protein catabolism. A prolonged PT is associated with stronger anomalies in pathways implicated in the pathogenesis of sepsis, suggesting that activation of coagulation impacts other host response mechanisms.


Ca2+ sensitization and PKC contribute to exercise training-enhanced contractility in porcine collateral-dependent coronary arteries.
Exercise training enhances endothelium-dependent coronary vasodilatation, improving perfusion and contractile function of collateral-dependent myocardium. Paradoxically, studies from our laboratory have revealed increased Ca(2+)-dependent basal active tone in collateral-dependent arteries of exercise-trained pigs. In this study, we tested the hypothesis that exercise training enhances agonist-mediated contractile responses of collateral-dependent arteries by promoting Ca(2+) sensitization. Ameroid constrictors were surgically placed around the proximal left circumflex coronary (LCX) artery of female Yucatan miniature pigs. Eight weeks postoperatively, pigs were randomized into sedentary (pen confined) or exercise-training (treadmill run; 5 days/wk; 14 wk) groups. Arteries (∼150 μm luminal diameter) were isolated from the collateral-dependent and nonoccluded (left anterior descending artery supplied) myocardial regions, and measures of contractile tension or simultaneous tension and intracellular free Ca(2+) concentration levels (fura-2) were completed. Exercise training enhanced contractile responses to endothelin-1 in collateral-dependent compared with nonoccluded arteries, an effect that was more pronounced in the presence of nitric oxide synthase inhibition (N(ω)-nitro-l-arginine methyl ester; 100 μM). Contractile responses to endothelin-1 were not altered by coronary occlusion alone. Exercise training produced increased tension at comparable levels of intracellular free Ca(2+) concentration in collateral-dependent compared with nonoccluded arteries, indicative of exercise training-enhanced Ca(2+) sensitization. Inhibition of PKC (calphostin C; 1 μM), but not Rho-kinase (Y-27632, 10 μM; or hydroxyfasudil, 30 μM), abolished the training-enhanced endothelin-1-mediated contractile response. Exercise training also increased sensitivity to the PKC activator phorbol 12,13-dibutyrate in collateral-dependent compared with nonoccluded arteries. Taken together, these data reveal that exercise training enhances endothelin-1-mediated contractile responses in collateral-dependent coronary arteries likely via increased PKC-mediated Ca(2+) sensitization.


CARMEN, a human super enhancer-associated long noncoding RNA controlling cardiac specification, differentiation and homeostasis.
Long noncoding RNAs (lncRNAs) are emerging as important regulators of developmental pathways. However, their roles in human cardiac precursor cell (CPC) remain unexplored. To characterize the long noncoding transcriptome during human CPC cardiac differentiation, we profiled the lncRNA transcriptome in CPCs isolated from the human fetal heart and identified 570 lncRNAs that were modulated during cardiac differentiation. Many of these were associated with active cardiac enhancer and super enhancers (SE) with their expression being correlated with proximal cardiac genes. One of the most upregulated lncRNAs was a SE-associated lncRNA that was named CARMEN, (CAR)diac (M)esoderm (E)nhancer-associated (N)oncoding RNA. CARMEN exhibits RNA-dependent enhancing activity and is upstream of the cardiac mesoderm-specifying gene regulatory network. Interestingly, CARMEN interacts with SUZ12 and EZH2, two components of the polycomb repressive complex 2 (PRC2). We demonstrate that CARMEN knockdown inhibits cardiac specification and differentiation in cardiac precursor cells independently of MIR-143 and -145 expression, two microRNAs located proximal to the enhancer sequences. Importantly, CARMEN expression was activated during pathological remodeling in the mouse and human hearts, and was necessary for maintaining cardiac identity in differentiated cardiomyocytes. This study demonstrates therefore that CARMEN is a crucial regulator of cardiac cell differentiation and homeostasis.


Cardiac effects of amodiaquine and sulfadoxine-pyrimethamine in malaria-infected African patients.
The cardiac effect of amodiaquine and sulfadoxine-pyrimethamine was studied in adult Cameroonian patients with acute uncomplicated Plasmodium falciparum malaria by electrocardiographic monitoring over the course of 7 days. Clinical and parasitological responses were monitored until Day 14. Bradycardia was observed in 16 of 20 amodiaquine-treated patients on Day 2, which corresponds to the time when maximal cumulative plasma concentration is reached, and in 12 of 20 patients on Day 7. A bradycardic effect lasting several days was not noted in patients treated with sulfadoxine-pyrimethamine. Significantly prolonged P, PQ, QRS, and QTc intervals were recorded on Day 2 after both 30 and 35 mg of amodiaquine base per kilogram of body weight had been administered, but these intervals were not correlated with the plasma monodesethylamodiaquine (main human active metabolite of amodiaquine) level. Electrocardiographic changes after therapy with sulfadoxine-pyrimethamine were minor and transient. All patients had fever and parasite clearance on or before Day 3 and remained free of fever and parasites until Day 14. None of the patients complained of cardiovascular adverse effects during the follow-up. These results suggest the absence of significant cardiac effects of amodiaquine and sulfadoxine-pyrimethamine at usual therapeutic doses, but they should draw the attention of clinicians treating malaria-infected patients who have taken other antimalarial drugs with cardiovascular side effects or those who are under treatment with cardiovascular drugs.


Propolis suppresses tumor angiogenesis by inducing apoptosis in tube-forming endothelial cells.
We have reported that propolis suppresses tumor-induced angiogenesis in vivo and in vitro, but antiangiogenic mechanism of propolis at cellular level remains unclear. In this study, we observed that propolis not only inhibited tube formation but also induced apoptosis of endothelial cells. These results suggest that propolis exerts its antiangiogenic effects at least in part through induction of apoptosis.


Automated Morphological Analysis of Microglia After Stroke.
Microglia are the resident immune cells of the brain and react quickly to changes in their environment with transcriptional regulation and morphological changes. Brain tissue injury such as ischemic stroke induces a local inflammatory response encompassing microglial activation. The change in activation status of a microglia is reflected in its gradual morphological transformation from a highly ramified into a less ramified or amoeboid cell shape. For this reason, the morphological changes of microglia are widely utilized to quantify microglial activation and studying their involvement in virtually all brain diseases. However, the currently available methods, which are mainly based on manual rating of immunofluorescent microscopic images, are often inaccurate, rater biased, and highly time consuming. To address these issues, we created a fully automated image analysis tool, which enables the analysis of microglia morphology from a confocal Z-stack and providing up to 59 morphological features. We developed the algorithm on an exploratory dataset of microglial cells from a stroke mouse model and validated the findings on an independent data set. In both datasets, we could demonstrate the ability of the algorithm to sensitively discriminate between the microglia morphology in the peri-infarct and the contralateral, unaffected cortex. Dimensionality reduction by principal component analysis allowed to generate a highly sensitive compound score for microglial shape analysis. Finally, we tested for concordance of results between the novel automated analysis tool and the conventional manual analysis and found a high degree of correlation. In conclusion, our novel method for the fully automatized analysis of microglia morphology shows excellent accuracy and time efficacy compared to traditional analysis methods. This tool, which we make openly available, could find application to study microglia morphology using fluorescence imaging in a wide range of brain disease models.


A potential benefit of albinism in Astyanax cavefish: downregulation of the oca2 gene increases tyrosine and catecholamine levels as an alternative to melanin synthesis.
Albinism, the loss of melanin pigmentation, has evolved in a diverse variety of cave animals but the responsible evolutionary mechanisms are unknown. In Astyanax mexicanus, which has a pigmented surface dwelling form (surface fish) and several albino cave-dwelling forms (cavefish), albinism is caused by loss of function mutations in the oca2 gene, which operates during the first step of the melanin synthesis pathway. In addition to albinism, cavefish have evolved differences in behavior, including feeding and sleep, which are under the control of the catecholamine system. The catecholamine and melanin synthesis pathways diverge after beginning with the same substrate, L-tyrosine. Here we describe a novel relationship between the catecholamine and melanin synthesis pathways in Astyanax. Our results show significant increases in L-tyrosine, dopamine, and norepinephrine in pre-feeding larvae and adult brains of Pachón cavefish relative to surface fish. In addition, norepinephrine is elevated in cavefish adult kidneys, which contain the teleost homologs of catecholamine synthesizing adrenal cells. We further show that the oca2 gene is expressed during surface fish development but is downregulated in cavefish embryos. A key finding is that knockdown of oca2 expression in surface fish embryos delays the development of pigmented melanophores and simultaneously increases L-tyrosine and dopamine. We conclude that a potential evolutionary benefit of albinism in Astyanax cavefish may be to provide surplus L-tyrosine as a precursor for the elevated catecholamine synthesis pathway, which could be important for adaptation to the challenging cave environment.


Trial of feasibility and acceptability of routine low-dose aspirin versus Early Screening Test indicated aspirin for pre-eclampsia prevention (TEST study): a multicentre randomised controlled trial.
Evaluate the feasibility and acceptability of routine aspirin in low-risk women, compared with screening-test indicated aspirin for the prevention of pre-eclampsia and fetal growth restriction. Multicentre open-label feasibility randomised controlled trial. Two tertiary maternity hospitals in Dublin, Ireland. 546 low-risk nulliparous women completed the study. Women underwent computerised randomisation to: Group 1-routine aspirin 75 mg from 11 until 36 weeks; Group 2-no aspirin and; Group 3-aspirin based on the Fetal Medicine Foundation screening test. PRIMARY AND SECONDARY OUTCOME MEASURES: (1) Proportion agreeing to participate; (2) compliance with protocol; (3) proportion where first trimester uterine artery Doppler was obtainable and; (4) time taken to issue a screening result. Secondary outcomes included rates of pre-eclampsia and small-for-gestational-age fetuses. 546 were included in the routine aspirin (n=179), no aspirin (n=183) and screen and treat (n=184) groups. 546 of 1054 were approached (51.8%) and enrolled. Average aspirin adherence was 90%. The uterine artery Doppler was obtained in 98.4% (181/184) and the average time to obtain a screening result was 7.6 (0-26) days. Of those taking aspirin, vaginal spotting was greater; n=29 (15.1%), non-aspirin n=28 (7.9%), OR 2.1 (95% CI 1.2 to 3.6). Postpartum haemorrhage >500 mL was also greater; aspirin n=26 (13.5%), no aspirin n=20 (5.6%), OR 2.6 (95% CI 1.4 to 4.8). Low-risk nulliparous women are open to taking aspirin in pregnancy and had high levels of adherence. Aspirin use was associated with greater rates of vaginal bleeding. An appropriately powered randomised controlled trial is now required to address the efficacy and safety of universal low-dose aspirin in low-risk pregnancy compared with a screening approach. ISRCTN (15191778); Post-results.


Breast Cancer Characteristics Associated With Digital Versus Film-Screen Mammography for Screen-Detected and Interval Cancers.
The purpose of this study was to determine whether pathologic findings of screen-detected and interval cancers differ for digital versus film mammography. Breast Cancer Surveillance Consortium data from 2003-2011 on 3,021,515 screening mammograms (40.3% digital, 59.7% film) of women 40-89 years old were reviewed. Cancers were considered screen detected if diagnosed within 12 months of an examination with positive findings and interval if diagnosed within 12 months of an examination with negative findings. Tumor characteristics for screen-detected and interval cancers were compared for digital versus film mammography by use of logistic regression models to estimate the odds ratio and 95% CI with adjustment for age, race and ethnicity, hormone therapy use, screening interval, examination year, and registry. Generalized estimating equations were used to account for correlation within facilities. Among 15,729 breast cancers, 85.3% were screen detected and 14.7% were interval. Digital and film mammography had similar rates of screen-detected (4.47 vs 4.42 per 1000 examinations) and interval (0.73 vs 0.79 per 1000 examinations) cancers for digital versus film. In adjusted analyses, interval cancers diagnosed after digital examinations with negative findings were less likely to be American Joint Committee on Cancer stage IIB or higher (odds ratio, 0.69; 95% CI, 0.52-0.93), have positive nodal status (odds ratio, 0.78; 95% CI, 0.64-0.95), or be estrogen receptor negative (odds ratio, 0.71; 95% CI, 0.56-0.91) than were interval cancers diagnosed after a film examination with negative findings. Screen-detected cancers diagnosed after digital and film mammography had similar rates of unfavorable tumor characteristics. Interval-detected cancers diagnosed after a digital examination were less likely to have unfavorable tumor features than those diagnosed after film mammography, but the absolute differences were small.


Forearm arterial compliance: the validation of a plethysmographic technique for the measurement of arterial compliance.
Arterial compliance was determined in eight normal subjects and 23 patients with hypertension and vascular disease by two independent techniques: (a) with a plethysmographic strain gauge (to measure pulsatile forearm volume changes as representing intra-arterial volume changes) and an automated sphygmomanometric system (to measure pulse pressure) and (b) calculation from the local pulse wave velocity and dimension of the brachial artery measured by pulsed wave Doppler ultrasound. Arterial compliance measured both by the plethysmographic technique and calculated from the pulse wave velocity was reduced in subjects with hypertension and vascular disease as compared with normal subjects. The regression equation between the compliance determined by the plethysmographic technique (x) and that calculated (y) from the pulse wave velocity and brachial arterial diameter was y = 3. 35x + 1.53, r = 0.77, P less than 0.001. The good correlation appears to validate the plethysmographic technique as a method of determining arterial compliance.


Impact of blue light filtering glasses on computer vision syndrome in radiology residents: a pilot study.
Computer vision syndrome (CVS) is an umbrella term for a pattern of symptoms associated with prolonged digital screen exposure, such as eyestrain, headaches, blurred vision, and dry eyes. Commercially available blue light filtering lenses (BLFL) are advertised as improving CVS. Our pilot study evaluates the effectiveness of BLFL on reducing CVS symptoms and fatigue in a cohort of radiologists. A prospective crossover study was conducted with ten radiology residents randomized into two cohorts: one wearing BLFL first then a sham pair (non-BLFL), and the other wearing a sham pair first then BLFL, over two weeks during normal clinical work. Participants filled out a questionnaire using the validated computer vision syndrome questionnaire (CVS-Q) and the Swedish Occupational Fatigue Inventory (SOFI). The majority of symptoms [11/16 (68.8%) and 13/16 (81.3%) symptoms on the CVS-Q and SOFI, respectively] were reduced (i.e., symptoms less severe) with the BLFL compared to the sham glasses. Females rated symptoms of sleepiness and physical discomfort in the SOFI, and overall CVS-Q, as more severe. Postgraduate year (PGY)-2 residents rated all symptoms as more severe than PGY-3/4s. BLFL may ameliorate CVS symptoms. Future studies with larger sample sizes and participants of different ages are required to verify the potential of BLFL.


Combined fibrinogen and neutrophil-lymphocyte ratio as a prognostic marker of advanced esophageal squamous cell carcinoma.
Patients with advanced esophageal squamous cell carcinoma (ESCC) is received chemoradiotherapy or chemotherapy for clinical management. However, it is difficult to predict tumor response and prognosis using blood markers before starting treatments. The purpose of this study was to investigate the pre-treatment plasma fibrinogen and neutrophil-lymphocyte ratio (NLR) in patients with advanced ESCC treated with chemoradiotherapy or chemotherapy, and to assess the clinical utility of a combined score using these blood markers, named as the F-NLR (fibrinogen and NLR) score, as a predictor of tumor response and prognosis. A total of 98 advanced ESCC patients, treated with chemoradiotherapy or chemotherapy, were classified into three groups: F-NLR score of 2, having both hyperfibrinogenemia (>400 mg/dL) and high NLR (>3.0), score of 1, one of these hematological abnormalities, and score of 0, having neither hyperfibrinogenemia nor high NLR. Fibrinogen and NLR were significantly higher in the progressive disease (PD) group than the non-PD group (P = 0.0419, and P = 0.0001, respectively). A significantly higher F-NLR score was found in the PD group than the non-PD group (P = 0.0140). Overall survival was significantly lower in patients with an F-NLR score of 2 than in those with an F-NLR score of 0 or 1 (P < 0.0001). Multivariate analysis showed that the F-NLR score was one of the independent prognostic factors (P = 0.0081). Our study demonstrates that the F-NLR score is promising as a predictive marker for therapeutic effects and prognosis in patients with advanced ESCC.


A theoretical elucidation of glucose interaction with HSA's domains.
The interaction of different domains belonging to Human Serum Albumin (HSA) with open form of glucose have been investigated using molecular dynamics simulation methods. Applying docking, primary structures involving interaction of some residues with glucose have been obtained. Subsequently, equilibrium geometries at 300 K and minimum geometries have been determined for each of aforementioned structures by employing MD simulation and simulated annealing. The stability of species has been evaluated using a SAWSA v2.0 model. Ultimately, NBO analysis has been carried out to specify possible hydrogen bonding regarding the HSA interaction with glucose. Results obtained show that glucose can interact with Lys195, Lys199, and Glu153. In these interactions, each lysine forms an H-bonding with glucose. The H-bonding is obtained by stretching of N-H bond belonging to NH(3)(+) group of lysine along an oxygen atom of glucose. In addition, the above mentioned lysines are protonated, and there is an electrostatic interaction between glucose with Lys195 or Lys199. In addition, an H-bonding is formed between O atom of -COO group belonging to Glu153 and H atom of OH group belonging to glucose. Because, the N-H group of Lys195 interacts with the O atom of latter OH group, reaction of Lys195 is more desirable than that of Lys199. In fact, glucose is placed in the vicinity of Lys195 along with electrostatic interaction and H-bonding to Lys195 and Lys199 as well as H-bonding with Glu153, which subsequently reacts with Lys195. Thus, Lys195 is the primary site in reaction of glucose with HSA.


Microfabricated platform for studying stem cell fates.
Platforms that allow parallel, quantitative analysis of single cells will be integral to realizing the potential of postgenomic biology. In stem cell biology, the study of clonal stem cells in multiwell formats is currently both inefficient and time-consuming. Thus, to investigate low-frequency events of interest, large sample sizes must be interrogated. We report a simple, versatile, and efficient micropatterned arraying system conducive to the culture and dynamic monitoring of stem cell proliferation. This platform enables: 1) parallel, automated, long-term ( approximately days to weeks), live-cell microscopy of single cells in culture; 2) tracking of individual cell fates over time (proliferation, apoptosis); and 3) correlation of differentiated progeny with founder clones. To achieve these goals, we used microfabrication techniques to create an array of approximately 10,000 microwells on a glass coverslip. The dimensions of the wells are tunable, ranging from 20 to >500 microm in diameter and 10-500 microm in height. The microarray can be coated with adhesive proteins and is integrated into a culture chamber that permits rapid (approximately min), addressable monitoring of each well using a standard programmable microscope stage. All cells share the same media (including paracrine survival signals), as opposed to cells in multiwell formats. The incorporation of a coverslip as a substrate also renders the platform compatible with conventional, high-magnification light and fluorescent microscopy. We validated this approach by analyzing the proliferation dynamics of a heterogeneous adult rat neural stem cell population. Using this platform, one can further interrogate the response of distinct stem cell subpopulations to microenvironmental cues (mitogens, cell-cell interactions, and cell-extracellular matrix interactions) that govern their behavior. In the future, the platform may also be adapted for the study of other cell types by tailoring the surface coatings, microwell dimensions, and culture environment, thereby enabling parallel investigation of many distinct cellular responses.


Verapamil, diltiazem and nifedipine block the depolarization-induced potentiation of norepinephrine contractions in rabbit aorta and porcine coronary arteries.
The effectiveness of verapamil, diltiazem and nifedipine in reducing potassium-induced enhancement of vascular responses to norepinephrine was studied in rabbit aorta and porcine coronary arteries. At multiple levels of external potassium concentration (4-28 mM), norepinephrine concentration-response curves were performed. Whereas the tissue was only slightly depolarized (about 5 mV) by an increase in external potassium to 20 mM, the norepinephrine response was markedly potentiated. For example, the EC50 of norepinephrine in aortic rings was reduced from 4.7 X 10(-8) M in 4 mM potassium to 4.7 X 10(-9) M in 20 mM potassium. Calcium channel blockers reduced potassium- and calcium-induced contractions, the IC50 being 6 X 10(-8) M for verapamil, 5 X 10(-7) M for diltiazem and 3 X 10(-9) M for nifedipine. These concentrations only minimally reduced norepinephrine contraction in 4 mM potassium but virtually abolished the depolarization-induced potentiation of the norepinephrine contraction. Even short exposures to levels of potassium, which resulted in little or no contraction by themselves, markedly potentiated the norepinephrine contraction. Therefore, the abolition of this potentiation by calcium channel blockers cannot be explained by a reduction of potassium-induced contraction. Similar observations were made in porcine coronary arteries. Thus, the potency of calcium channel blockers against norepinephrine-induced contractions is markedly increased in depolarized vascular smooth muscle. Calcium channel blockers may be especially effective in preventing enhanced vascular contractions resulting from physiological concentrations of catecholamines in partially depolarized vascular smooth muscle.


Value of Contrast-Enhanced MRA versus Time-of-Flight MRA in Acute Ischemic Stroke MRI.
Vessel imaging in acute ischemic stroke is essential to select patients with large-vessel occlusion for mechanical thrombectomy. Our aim was to compare the diagnostic accuracy of time-of-flight MR angiography and contrast-enhanced MR angiography for identification of vessel occlusion and collateral status in acute ischemic stroke. One hundred twenty-three patients with stroke with large-vessel occlusion before thrombectomy were included in this retrospective study. Before thrombectomy, 3T MR imaging, including conventional 3D TOF-MRA of the intracranial arteries and contrast-enhanced MRA of intra- and extracranial arteries, was performed. Both techniques were assessed independently by 2 neuroradiologists for location of the occlusion, imaging quality, and collateral status. Findings were compared, with subsequent DSA as the reference standard. Both techniques had good interrater agreement of κ = 0.74 (95% CI, 0.66-0.83) for TOF-MRA and κ = 0.72 (95% CI, 0.63-0.80) for contrast-enhanced MRA. Occlusion localization differed significantly on TOF-MRA compared with DSA (P < .001), while no significant difference was observed between DSA and contrast-enhanced MRA (P = .75). Assessment of collaterals showed very good agreement between contrast-enhanced MRA and DSA (94.9% with P = .25), but only fair agreement between TOF-MRA and DSA (23.2% with P < .001). Contrast-enhanced MRA offers better diagnostic accuracy than TOF-MRA in acute ischemic stroke. Contrast-enhanced MRA was superior in localizing vessel occlusion within a shorter acquisition time while providing a larger coverage, including extracranial vessels, and a more accurate assessment of collateral status. These results support inclusion of contrast-enhanced MRA in acute stroke MR imaging, perhaps making TOF-MRA superfluous.


Potent and specific inhibition of mMate1-mediated efflux of type I organic cations in the liver and kidney by pyrimethamine.
This report describes a potent and selective inhibitor of multidrug and toxin extrusion (MATE) protein, pyrimethamine (PYR), and examines its effect on the urinary and biliary excretion of typical Mate1 substrates in mice. In vitro inhibition studies demonstrated that PYR is a potent inhibitor of mouse (m)Mate1 (K(i) = 145 nM) among renal organic cation transporters mOctn1 and mOctn2 (K(i) > 30 microM), mOct1 (K(i) = 3.6 microM), and mOct2 (K(i) = 6.0 microM). PYR inhibited the uptake of metformin by kidney brush-border membrane vesicles (BBMVs) (K(i) = 41 nM) and canalicular membrane vesicles in the presence of outward gradient of H+. PYR treatment significantly increased the kidney-to-plasma ratio of tetraethylammonium, and both the liver- and kidney-to-plasma ratios of metformin in mice, whereas it did not affect their plasma concentrations and urinary excretion rates. Furthermore, the plasma lactate concentration, a biomarker for inhibition of gluconeogenesis by metformin, was significantly higher in the PYR-treated group than in the control group. These results not only suggest the importance of mMate1 in the efflux of organic cations into the urine and bile in mice but also the importance of canalicular efflux mediated by MATE proteins for the therapeutic efficacy of metformin. PYR is a potent inhibitor of human (h)MATE1 and hMATE2-K (K(i) = 77 and 46 nM, respectively) and H+ and organic cation exchanger in human kidney BBMVs (K(i) = 31 nM) in the presence of outward gradient of H+. Taken together, PYR can be used as a potent probe inhibitor of human MATE transporters.


Global mapping of Al, Cu, Fe, and Zn in-use stocks and in-ground resources.
Human activity has become a significant geomorphic force in modern times, resulting in unprecedented movements of material around Earth. An essential constituent of this material movement, the major industrial metals aluminium, copper, iron, and zinc in the human-built environment are mapped globally at 1-km nominal resolution for the year 2000 and compared with the locations of present-day in-ground resources. While the maps of in-ground resources generated essentially combine available databases, the mapping methodology of in-use stocks relies on the linear regression between gross domestic product and both in-use stock estimates and the Nighttime Lights of the World dataset. As the first global maps of in-use metal stocks, they reveal that a full 25% of the world's Fe, Al, Cu, and Zn in-use deposits are concentrated in three bands: (i) the Eastern seaboard from Washington, D.C. to Boston in the United States, (ii) England, Benelux into Germany and Northern Italy, and (iii) South Korea and Japan. This pattern is consistent across all metals investigated. In contrast, the global maps of primary metal resources reveal these deposits are more evenly distributed between the developed and developing worlds, with the distribution pattern differing depending on the metal. This analysis highlights the magnitude at which in-ground metal resources have been translocated to in-use stocks, largely from highly concentrated but globally dispersed in-ground deposits to more diffuse in-use stocks located primarily in developed urban regions.


Use of green fluorescent protein color variants expressed on stable broad-host-range vectors to visualize rhizobia interacting with plants.
We developed two sets of broad-host-range vectors that drive expression of the green fluorescent protein (GFP) or color variants thereof (henceforth collectively called autofluorescent proteins [AFPs]) from the lac promoter. These two sets are based on different replicons that are maintained in a stable fashion in Escherichia coli and rhizobia. Using specific filter sets or a dedicated confocal laser scanning microscope setup in which emitted light is split into its color components through a prism, we were able to unambiguously identify bacteria expressing enhanced cyan fluorescent protein (ECFP) or enhanced yellow fluorescent protein (EYFP) in mixtures of the two. Clearly, these vectors will be valuable tools for competition, cohabitation, and rescue studies and will also allow the visualization of interactions between genetically marked bacteria in vivo. Here, we used these vectors to visualize the interaction between rhizobia and plants. Specifically, we found that progeny from different rhizobia can be found in the same nodule or even in the same infection thread. We also visualized movements of bacteroids within plant nodule cells.


Evaluation of diffusive gradients in thin films technique (DGT) for measuring Al, Cd, Co, Cu, Mn, Ni, and Zn in Amazonian rivers.
Studies concerning the lability and bioavailability of trace metals have played a prominent role in the search for contamination of water resources. This work describes the first application yet of the diffusive gradients in thin films technique (DGT) to the determination of the fraction of free plus labile metals in waters from the Amazon Basin. Due to the complexity of the use of DGT for samples with low ionic strength and high organic matter content (characteristic of Amazonian rivers), a new analytical procedure was developed. The method is based on the determinations of apparent diffusion coefficients (Dap) in the laboratory, by performing deployments in samples collected in the corresponding sites of study. The Dap thereby determined is then used for in situ measurements. The suitability of the proposed approach for determination of labile Al, Cd, Co, Cu, Mn, Ni, and Zn in the Amazon River and Rio Negro (English: Black River) was evaluated. Except for Co, Mn (in a deployment at Rio Negro), Ni and Zn (in a deployment at Amazon River), labile in situ measurements were lower or similar to dissolved concentrations, indicating suitability of the proposed approach.


Design concepts in absorbance optical systems for analytical ultracentrifugation.
Analytical ultracentrifugation is a powerful technique for analyzing particles in solution, and has proved valuable for a wide range of applications in chemistry, biochemistry and material sciences for many years. The field is presently seeing a resurgence of instrument development from commercial and academic groups. To date, no modern optical modeling techniques have ever been applied to the basic imaging properties of the optical system in analytical ultracentrifugation. In this manuscript we provide a contextual framework for the application of such techniques, including an overview of the essential optical principles. The existing commercial and open source detection systems are evaluated for imaging performance, highlighting the limitations of chromatic aberration for broadband acquisitions. These results are the inspiration for a new mirror-based design, free of chromatic aberration. Our findings present a path forward for continued development in imaging and detector technology, where improved data quality will now push the limits of detection and resolution of analytical ultracentrifugation for years to come.


Complications associated with stellate ganglion nerve block: a systematic review.
Stellate ganglion nerve blockade (SGNB) is a vital tool in our armamentarium for the treatment of various chronic pain syndromes. SGNB can be performed using the traditional landmark-based approach, or with image guidance using either fluoroscopy or ultrasound. In this review, we systematically analyzed reported SGNB-related complications between 1990 and 2018. Seven databases were queried for SGNB between January 1, 1990 and November 27, 2018. Search results of the complications associated with SGNB were reported as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations. Out of a total of 1909 articles, 67 articles met our inclusion criteria, yielding 260 cases with adverse events. In 134 of the 260 (51.5%) cases, SGNB was performed with image guidance. Sixty-four (24.6%) and 70 (26.9%) of the complication cases reported the use of ultrasound and fluoroscopy guidance, respectively. One hundred and seventy-eight (68.4%) patients had medication-related or systemic side effects, and 82 (31.5%) had procedure-related or local side effects. There was one report of death due to massive hematoma leading to airway obstruction. There was one case report of quadriplegia secondary to pyogenic cervical epidural abscess and discitis following an SGNB. Complications following SGNB have been reported with both landmark-based techniques and with imaging guidance using fluoroscopy or ultrasound. In our systematic review, most adverse events that were reported occurred during or shortly after SGNB. Vigilance, American Society of Anesthesiologists standard monitors for conscious sedation, and accessibility to resuscitation equipment are vital to the safe performance of SGNB.


Role of pilA, an essential regulatory gene of Neisseria gonorrhoeae, in the stress response.
Sequence analysis has shown that PilA, a transcriptional regulator of pilin gene expression in Neisseria gonorrhoeae, has extensive homology with the 54-kDa protein of the signal recognition particle of eukaryotes and its receptor, as well as with two proteins of Escherichia coli, FtsY and Ffh, which have been proposed to be a part of a signal recognition particle-like apparatus. We tested the putative role of PilA in protein export in N. gonorrhoeae and did not find any effect. However, we did observe induction of a heat shock response and a previously described slow-growth phenotype when PilA function was impaired. We also examined the interference of pilA expression in E. coli with the function of the products of ftsY and ffh and observed an accumulation of pre-beta-lactamase. We argue against a direct role for PilA in protein export in gonococci and propose instead that PilA is involved in the modulation of cell growth rate in response to different environmental conditions.


Lack of transmission of human immunodeficiency virus from infected children to their household contacts.
The possibility of transmission of the human immunodeficiency virus (HIV) from infected children to their contacts has been confronted in households, schools, day-care centers, and other child care settings. Cases reported to the Centers for Disease Control and several studies of close contacts of HIV-infected patients suggested that the risk of transmission in these settings is extremely low. However, most of these studies involved infected adults or older children. Younger children, who drool, bite, mouth toys, and are incontinent, may be more likely to transmit HIV in these settings. To assess this possibility, the authors tested 89 members of households in which 25 children with HIV infection, most of whom were preschool-aged, resided. Household members had close personal contact with the infected children. They shared many items likely to be soiled with blood and body fluids, such as toys, toothbrushes, eating utensils, toilets, and bathtubs. Hugging, kissing, sharing a bed, and bathing together were common. Household members were tested no sooner than 4 months after initial contact with the infected child, to allow adequate time for sero-conversion. All 89 participating household members were anti-HIV seronegative, and 78 who were tested were serum p24 antigen negative. It was concluded from this study and other evidence that the risk of transmission from children to their contacts is extremely low and has not been clearly documented in the household setting.


Acarbose has sex-dependent and -independent effects on age-related physical function, cardiac health, and lipid biology.
With an expanding aging population burdened with comorbidities, there is considerable interest in treatments that optimize health in later life. Acarbose (ACA), a drug used clinically to treat type 2 diabetes mellitus (T2DM), can extend mouse life span with greater effect in males than in females. Using a genetically heterogeneous mouse model, we tested the ability of ACA to ameliorate functional, pathological, and biochemical changes that occur during aging, and we determined which of the effects of age and drug were sex dependent. In both sexes, ACA prevented age-dependent loss of body mass, in addition to improving balance/coordination on an accelerating rotarod, rotarod endurance, and grip strength test. Age-related cardiac hypertrophy was seen only in male mice, and this male-specific aging effect was attenuated by ACA. ACA-sensitive cardiac changes were associated with reduced activation of cardiac growth-promoting pathways and increased abundance of peroxisomal proteins involved in lipid metabolism. ACA further ameliorated age-associated changes in cardiac lipid species, particularly lysophospholipids - changes that have previously been associated with aging, cardiac dysfunction, and cardiovascular disease in humans. In the liver, ACA had pronounced effects on lipid handling in both sexes, reducing hepatic lipidosis during aging and shifting the liver lipidome in adulthood, particularly favoring reduced triglyceride (TAG) accumulation. Our results demonstrate that ACA, already in clinical use for T2DM, has broad-ranging antiaging effects in multiple tissues, and it may have the potential to increase physical function and alter lipid biology to preserve or improve health at older ages.


Effects of 6-hydroxydopamine on hemodynamic function in the pithed rat.
The effects of 6-hydroxydopamine (6-HDA) on hemodynamic function were assessed in pithed male Sprague-Dawley rats prepared for continuous measurement of cardiac output by electromagnetic flowmetry. One week after 6-HDA administration, 100 mg/kg s.c., blood pressure increments elicited by electrical stimulation of the lumbar sympathetic outflow (0.25-8.0 Hz) were reduced significantly (P less than .01), whereas heart rate responses were normal. The reduction in blood pressure responses was due to an attenuation of increases in both cardiac output (P less than .01) and total peripheral resistance (P less than .02). Cardiac output responses were reduced exclusively due to a fall in stroke volume inasmuch as heart rate increases were not altered by 6-HDA. Furthermore, the reduction in neurally mediated cardiac output increases by 6-HDA appeared to result from impaired sympathetic control of inotropic activity. This conclusion was supported by the observation that pretreatment with the beta adrenergic receptor antagonist, nadolol, markedly decreased cardiac output responses in control animals, but did not further attenuate cardiac output increases in 6-HDA-treated rats. However, after nadolol a substantial cardiac output response remained that was equivalent in 6-HDA-treated and control rats. This remaining response may be accounted for by venous constriction and because there was no difference in the cardiac output increases in the two groups after nadolol it appears that neural control of venoconstriction was not impaired by 6-HDA. Thus results of the present study indicate that at 1 week after 6-HDA treatment noradrenergic control of resistance vessels and cardiac inotropism are reduced significantly.(ABSTRACT TRUNCATED AT 250 WORDS)


Neural and hypophyseal colloid deposition in the collared lemming.
Feral and captive lemmings from Churchill, Manitoba, are subject to a unique pathological process in which colloidal material is deposited in bloodvessel walls at scattered points through the central nervous system. Destruction of nervous tissue at these foci is progressive, and colloidal masses in the vascular lumina of the hypothalamus appear to become fixed in the capillaries of the hypophyseal anterior lobe. Inflammatory reactions are never associated with the lesions, and the latter are larger and more numerous in older animals in warmer environments.


Pasture allowance, duration, and stage of lactation-Effects on early and total lactation animal performance.
Pasture availability in early spring can be limited due to climatic effects on grass production, increasing the likelihood of feed deficits in early lactation of spring-calving pasture-based systems. We hypothesized that restricting pasture allowance (PA) when animals are at peak milk production will have more negative implications on milk production compared with restricting animals before this period. A total of 105 cows were assigned to 1 of 7 grazing treatments from March 14 to October 31, 2016 (33 wk). The control treatment was offered a PA to achieve a postgrazing sward height > 3.5 cm and mean pasture allowance of 15.5 kg of dry matter per cow. The remaining treatments were offered a PA representing 60% of that offered to the control for a duration of 2 or 6 wk from March 14 (mid-March; MMx2 and MMx6), March 28 (end of March; EMx2 and EMx6), or April 11 (mid-April; MAx2 and MAx6). Within grazing treatment, animals were also assigned to 1 of 2 calving dates (early and late) based on days in milk (DIM) on March 14. Early calved (EC) cows were ≥36 DIM, while late calved (LC) were ≤35 DIM. Restricting PA for 2 and 6 wk reduced daily milk yield (-1.6 and -2.2 kg/cow, respectively), cumulative milk protein yield (-4.0 and -6.3 kg/cow, respectively), and cumulative milk solids yield (-5.8 and -9.5 kg/cow, respectively) in the first 10 wk of the experiment. Daily milk yield was similar across the treatments at the end of the 33-wk period (16.8 kg/cow, average of all treatments), as was daily milk solids yield (1.40 kg/cow). Cows in the EC group produced less milk over the first 10 wk of the experiment (20.0 kg/cow per day) compared with the LC animals (22.1 kg/cow per day). However, body weight was greater (+15 kg/cow) in the EC animals compared with the LC, while body condition score was similar (2.85). This outcome indicates that animals that are restricted later in early lactation (circa onset of peak milk production) partition a greater proportion of available energy to maintenance, resulting in greater losses in milk production. These data indicate that despite the immediate reduction in milk production, restricting intake of grazing cows to 80% of that required to achieve spring grazing targets for postgrazing sward height for up to 6 wk may be used as a method of managing short-term pasture deficits on farm with minimal effects on total lactation performance.


Tolerance to parenchymal self. Regulatory role of major histocompatibility complex-restricted, OX8+ suppressor T cells specific for autologous renal tubular antigen in experimental interstitial nephritis.
BN rats develop interstitial nephritis after immunization with rabbit, but not rat renal tubular antigen. Using RT1n rat strains that differentially express tubular antigen, we investigated the unresponsiveness of BN rats to BN tubular antigen (BN-TBM) using delayed-type hypersensitivity (DTH) responses to BN-TBM as a measure of cell-mediated immunity. Our results indicate that rat strains expressing tubular antigen respond to immunization with BN-TBM with the clonal expansion of antigen-specific, cyclophosphamide-sensitive, OX8+, MHC-restricted suppressor T cells. Such suppression appears to be relevant to the maintenance of tolerance to parenchymal self, since chronic cyclophosphamide therapy abrogates suppression and results in significant interstitial nephritis.


State policies targeting junk food in schools: racial/ethnic differences in the effect of policy change on soda consumption.
We estimated the association between state policy changes and adolescent soda consumption and body mass index (BMI) percentile, overall and by race/ethnicity. We obtained data on whether states required or recommended that schools prohibit junk food in vending machines, snack bars, concession stands, and parties from the 2000 and 2006 School Health Policies and Programs Study. We used linear mixed models to estimate the association between 2000-2006 policy changes and 2007 soda consumption and BMI percentile, as reported by 90 730 students in 33 states and the District of Columbia in the Youth Risk Behavior Survey, and to test for racial/ethnic differences in the associations. Policy changes targeting concession stands were associated with 0.09 fewer servings of soda per day among students (95% confidence interval [CI] = -0.17, -0.01); the association was more pronounced among non-Hispanic Blacks (0.19 fewer servings per day). Policy changes targeting parties were associated with 0.07 fewer servings per day (95% CI = -0.13, 0.00). Policy changes were not associated with BMI percentile in any group. State policies targeting junk food in schools may reduce racial/ethnic disparities in adolescent soda consumption, but their impact appears to be too weak to reduce adolescent BMI percentile.


Evolutionary view of acyl-CoA diacylglycerol acyltransferase (DGAT), a key enzyme in neutral lipid biosynthesis.
Triacylglycerides (TAGs) are a class of neutral lipids that represent the most important storage form of energy for eukaryotic cells. DGAT (acyl-CoA: diacylglycerol acyltransferase; EC 188.8.131.52) is a transmembrane enzyme that acts in the final and committed step of TAG synthesis, and it has been proposed to be the rate-limiting enzyme in plant storage lipid accumulation. In fact, two different enzymes identified in several eukaryotic species, DGAT1 and DGAT2, are the main enzymes responsible for TAG synthesis. These enzymes do not share high DNA or protein sequence similarities, and it has been suggested that they play non-redundant roles in different tissues and in some species in TAG synthesis. Despite a number of previous studies on the DGAT1 and DGAT2 genes, which have emphasized their importance as potential obesity treatment targets to increase triacylglycerol accumulation, little is known about their evolutionary timeline in eukaryotes. The goal of this study was to examine the evolutionary relationship of the DGAT1 and DGAT2 genes across eukaryotic organisms in order to infer their origin. We have conducted a broad survey of fully sequenced genomes, including representatives of Amoebozoa, yeasts, fungi, algae, musses, plants, vertebrate and invertebrate species, for the presence of DGAT1 and DGAT2 gene homologs. We found that the DGAT1 and DGAT2 genes are nearly ubiquitous in eukaryotes and are readily identifiable in all the major eukaryotic groups and genomes examined. Phylogenetic analyses of the DGAT1 and DGAT2 amino acid sequences revealed evolutionary partitioning of the DGAT protein family into two major DGAT1 and DGAT2 clades. Protein secondary structure and hydrophobic-transmembrane analysis also showed differences between these enzymes. The analysis also revealed that the MGAT2 and AWAT genes may have arisen from DGAT2 duplication events. In this study, we identified several DGAT1 and DGAT2 homologs in eukaryote taxa. Overall, the data show that DGAT1 and DGAT2 are present in most eukaryotic organisms and belong to two different gene families. The phylogenetic and evolutionary analyses revealed that DGAT1 and DGAT2 evolved separately, with functional convergence, despite their wide molecular and structural divergence.


The association of race, comorbid anxiety, and antidepressant adherence among Medicaid enrollees with major depressive disorder.
Depressed patients often have comorbid anxiety. African-Americans with depression are less likely to adhere to antidepressant treatment. Knowledge of the association between race, comorbid anxiety, and adherence among Medicaid enrollees with depression is limited. The objective of this study was to evaluate the association of race, comorbid anxiety, and antidepressant adherence, and persistence among Medicaid enrollees with major depressive disorder (MDD). The MarketScan Multi-State Medicaid Database (Thomson Reuters, Ann Arbor, MI) was used in this retrospective cross-sectional study. Medicaid enrollees aged between 18 and 64 years, with MDD but without bipolar disorders, and with a newly initiated antidepressant between January 1, 2004 and December 31, 2006 were identified. An index date was assigned corresponding to the newly initiated antidepressant. Patients having claims for any antidepressant refills during the 12 months before the index date were excluded. Eligible patients were then followed-up for 12 months after the index date. Adherence was measured by a modified medication possession ratio. Adherence was evaluated using multivariate logistic regression. Persistence was assessed based on treatment discontinuation and examined by Kaplan-Meier survival curves and Cox-propositional hazard regression models. A total of 3083 Medicaid patients with MDD were included. Approximately, 25% of patients had comorbid anxiety. The odds of adhering to antidepressants were 40% lower among African-Americans than Caucasians, adjusting for covariates (AOR [adjust odds ratio]=0.60; 95% confidence interval [CI]=0.51-0.72, P<.001). MDD patients with comorbid anxiety were more likely to adhere to antidepressants than patients with MDD alone (AOR=1.55, 95% CI=1.27-1.90, P<.001). African-Americans had a higher hazard of not persistently taking antidepressants (hazard ratio=1.47, 95% CI=1.30-1.65, P<.001). The interaction between race and comorbid anxiety was not associated with adherence or persistence. Among Medicaid enrollees with MDD, race and comorbid anxiety disorders are significantly associated with antidepressant adherence and persistence. Physicians need to recognize comorbid anxiety and race as 2 important determinants of antidepressant use behaviors when they encounter Medicaid patients with MDD.


Three metallic BN polymorphs: 1D multi-threaded conduction in a 3D network.
In this paper, three novel metallic sp2/sp3-hybridized boron nitride (BN) polymorphs are proposed by first-principles calculations. One of them, denoted as tP-BN, is predicted based on the evolutionary particle swarm structural search. tP-BN is composed of two interlocked rings forming a tube-like 3D network. The stability and band structure calculations show that tP-BN is metastable and metallic at zero pressure. Calculations for the density of states and electron orbitals confirm that the metallicity originates from the sp2-hybridized B and N atoms, forming 1D linear conductive channels in the 3D network. According to the relationship between the atomic structure and electronic properties, another two 3D metastable metallic sp2/sp3-hybridized BN structures are constructed manually. Electronic property calculations show that both of these structures have 1D conductive channels along different axes. The polymorphs predicted in this study enrich the structures and provide a different picture of the conductive mechanism of BN compounds.


Pre-clinical In Vitro and In Vivo Models for Heart Valve Therapies.
Heart valve disease is a frequently encountered pathology, related to high morbidity and mortality rates. Animal models are interesting to investigate the causality but also underlying mechanisms and potential treatments of human heart valve diseases. Strongly believing that both in vivo and ex vivo models are fundamental to support research and development of new technologies, we here report some examples of heart valve disease models, which in our experience have been actively used to support the development of new valve therapies.


Extra-motor abnormalities in amyotrophic lateral sclerosis: another layer of heterogeneity.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease defined by the presence of muscle weakness. The motor features of disease are heterogeneous in site of onset and progression. There are also extra-motor features in some patients. The genetic basis for extra-motor features is uncertain. The heterogeneity of ALS is an issue for clinical trials. Areas covered: This paper reviews the range and prevalence of extra-motor features associated with ALS, and highlights the current information about genetic associations with extra-motor features. Expert commentary: There are extra-motor features of ALS, but these are not found in all patients. The most common is cognitive abnormality. More data is required to ascertain whether extra-motor features arise with progression of disease. Extra-motor features are reported in patients with a range of causative genetic mutations, but are not found in all patients with these mutations. Further studies are required of the heterogeneity of ALS, and genotype/phenotype correlations are required, taking note of extra-motor features.


Caloric restriction reduces cell loss and maintains estrogen receptor-alpha immunoreactivity in the pre-optic hypothalamus of female B6D2F1 mice.
Life-long calorie restriction (CR) remains the most robust and reliable means of extending life span in mammals. Among the several theories to explain CR actions, one variant of the neuroendocrine theories of aging postulates that changing hypothalamic sensitivity to endocrine feedback is the clock that times phenotypic change over the life span. If the feedback sensitivity hypothesis is correct, CR animals should display a significantly different pattern of hormone-sensitive cell density and distribution in the hypothalamus. Of the many endocrine signal receptors that may be involved in maintaining hypothalamic feedback sensitivity, our study has selected to begin mapping those for estrogen (E). Altered hypothalamic sensitivity to E is known to schedule reproductive maturation and influence reproductive senescence. Taking estrogen receptor-alpha (ERalpha) immunoreactivity as an index of sensitivity to E, we counted ERalpha immunoreactive and non-immunoreactive cells in the pre-optic hypothalamus of young (6 weeks), ad-libitum (Old-AL) fed old (22 months), and calorie restricted (Old-CR) old (22 months) female B6D2F1 mice. An automated imaging microscopy system (AIMS) was used to generate cell counts for each sampled section of pre-optic hypothalamus. Results show a 38% reduction in ERalpha immunoreactive cells and an 18% reduction in total cell numbers in AL-old mice in comparison to young mice. However, CR mice only show a 19% reduction in ERalpha immunoreactive cells and a 13% reduction in total cell numbers in comparison to young mice. This indicates CR prevents age-related cell loss and maintains estrogen sensitivity in the pre-optic hypothalamus of old female B6D2F1 mice.


Surface modification of grains with silver nano-clusters: a new route to great enhancement of photoluminescence in Eu³⁺-doped ferroelectric polycrystalline oxide thin films.
We report on a new route to greatly enhance the photoluminescence of Eu³⁺ doped ferroelectric polycrystalline oxide thin films: surface modification of grains with silver nanoclusters (NCs). The Ag doped Bi₃.₆Eu₀.₄Ti₃O₁₂ (BET) thin films were prepared by a chemical solution deposition method. According to the XRD, TEM and XPS analysis, partially oxidated Ag NCs have been formed on the surfaces of the BET grains. A greatly enhanced photoluminescence was obtained in a wide range of Ag doping level. Role of the Ag NCs in the photoluminescence enhancement was investigated by means of absorption, emission and excitation spectra, as well as decay lifetime measurement. The results indicate that the intra-4f transition of Eu³⁺ can be intensively activated by the coupling of the charge transfer band of BET with the ⁵D₀ state of Eu³⁺ ions, and the enhancement of Eu³⁺ ions emission in the present thin films was attributed to the surface modification of BET crystalline grains by Ag NCs. In addition, the influences of Ag NCs on the dielectric and ferroelectric properties of these materials were discussed as well.


Curcumin induces apoptosis in human non-small cell lung cancer NCI-H460 cells through ER stress and caspase cascade- and mitochondria-dependent pathways.
It has been reported that curcumin inhibited various types of cancer cells in vitro and in vivo. However, mechanisms of curcumin-inhibited cell growth and -induced apoptosis in human non-small cell lung cancer cells (NCI-H460) still remain unclear. In this study, NCI-H460 cells were treated with curcumin to determine its anticancer activity. Different concentrations of curcumin were used for different durations in NCI-H460 cells and the subsequent changes in the cell morphology, viability, cell cycle, mRNA and protein expressions were determined. Curcumin induced apoptotic morphologic changes in NCI-H460 cells in a dose-dependent manner. After curcumin treatment, BAX and BAD were up-regulated, BCL-2, BCL-X(L) and XIAP were down-regulated. In addition, reactive oxygen species (ROS), intracellular Ca(2+) and endoplasmic reticulum (ER) stress were increased in NCI-H460 cells after exposure to curcumin. These signals led to a loss of mitochondrial membrane potential (Delta Psi(m)) and culminated in caspase-3 activation. Curcumin-induced apoptosis was also stimulated through the FAS/caspase-8 (extrinsic) pathway and ER stress proteins, growth arrest- and DNA damage-inducible gene 153 (GADD153) and glucose-regulated protein 78 (GRP78) were activated in the NCI-H460 cells. Apoptotic cell death induced by curcumin was significantly reversed by pretreatment with ROS scavenger or caspase-8 inhibitor. Furthermore, the NCI-H460 cells tended to be arrested at the G(2)/M cell cycle stage after curcumin treatment and down-regulation of cyclin-dependent kinase 1 (CDK1) may be involved. In summary, curcumin exerts its anticancer effects on lung cancer NCI-H460 cells through apoptosis or cell cycle arrest.


Weight-loss induced changes in plasma factor VII coagulant activity and relation to the factor VII Arg/Gln353 polymorphism in moderately obese adults.
Elevated plasma factor VII coagulant activity (factor VIIc) may be an independent risk factor for coronary heart disease. Several cross-sectional studies suggest that a polymorphism of the factor VII gene (Arg-Gln353) interacts with plasma triglyceride level in determining factor VIIc, but prospective data are lacking. Factor VII genotype, factor VIIc, and triglyceride level were measured in moderately obese adults aged 25 to 45 who underwent a six-month clinical trial to evaluate strategies for weight loss. A total of 48 men and 50 women who experienced substantial weight loss (mean: 10 kg) provided samples for genetic analysis. Overall, 78% of participants were homozygous for the Arg353 allele, while the remaining 22% were heterozygous (Arg/Gln353). At the baseline examination, heterozygotes had lower mean factor VIIc than Arg353 homozygotes (92% vs. 112%; p<0.001), and genotype explained 18% of the variance of factor VIIc. Average six-month weight loss was similar in both genotypes; mean reductions in factor VIIc following weight loss were greatest among Arg353 homozygotes with high initial values (> 120%). Cross-sectional and longitudinal associations between plasma factor VIIc and triglyceride level were not dependent on genotype. These data confirm that the Gln353 allele is associated with lower factor VII coagulant activity in moderately obese adults, but they do not support the hypothesis that the Arg-Gln353 polymorphism interacts with plasma triglyceride level in determining factor VIIc.


State-of-the-art: Radiological investigation of pleural disease.
Pleural disease is common. Radiological investigation of pleural effusion, thickening, masses, and pneumothorax is key in diagnosing and determining management. Conventional chest radiograph (CXR) remains as the initial investigation of choice for patients with suspected pleural disease. When abnormalities are detected, thoracic ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) can each play important roles in further investigation, but appropriate modality selection is critical. US adds significant value in the identification of pleural fluid and pleural nodularity, guiding pleural procedures and, increasingly, as "point of care" assessment for pneumothorax, but is highly operator dependent. CT scan is the modality of choice for further assessment of pleural disease: Characterising pleural thickening, some pleural effusions and demonstration of homogeneity of pleural masses and areas of fatty attenuation or calcification. MRI has specific utility for soft tissue abnormalities and may have a role for younger patients requiring follow-up serial imaging. MRI and PET/CT may provide additional information in malignant pleural disease regarding prognosis and response to therapy. This article summarises existing techniques, highlighting the benefits and applications of these different imaging modalities and provides an up to date review of the evidence.


Cochrane Rehabilitation: 2019 annual report.
During its third year of existence, Cochrane Rehabilitation goals included to point out the main methodological issues in rehabilitation research, and to increase the Knowledge Translation activities. This has been performed through its committees and specific projects. In 2019, Cochrane Rehabilitation worked on five different special projects at different stages of development: 1) a collaboration with the World Health Organization to extract the best evidence for Rehabilitation (Be4rehab); 2) the development of a reporting checklist for Randomised Controlled Trials in rehabilitation (RCTRACK); 3) the definition of what is the rehabilitation for research purposes; 4) the ebook project; and 5) a prioritization exercise for Cochrane Reviews production. The Review Committee finalized the screening and "tagging" of all rehabilitation reviews in the Cochrane library; the Publication Committee increased the number of international journals with which publish Cochrane Corners; the Education Committee continued performing educational activities such as workshops in different meetings; the Methodology Committee performed the second Cochrane Rehabilitation Methodological Meeting and published many papers; the Communication Committee spread the rehabilitation evidence through different channels and translated the contents in different languages. The collaboration with several National and International Rehabilitation Scientific Societies, Universities, Hospitals, Research Centers and other organizations keeps on growing.


Needed: Global Collaboration for Comparative Research on Cities and Health.
Over half of the world's population lives in cities and United Nations (UN) demographers project an increase of 2.5 billion more urban dwellers by 2050. Yet there is too little systematic comparative research on the practice of urban health policy and management (HPAM), particularly in the megacities of middle-income and developing nations. We make a case for creating a global database on cities, population health and healthcare systems. The expenses involved in data collection would be difficult to justify without some review of previous work, some agreement on indicators worth measuring, conceptual and methodological considerations to guide the construction of the global database, and a set of research questions and hypotheses to test. We, therefore, address these issues in a manner that we hope will stimulate further discussion and collaboration.


Yaba monkey tumor virus encodes a functional inhibitor of interleukin-18.
Interleukin-18 (IL-18) is a critical proinflammatory cytokine whose extracellular bioactivity is regulated by a cellular IL-18 binding protein (IL-18BP). Many poxviruses have acquired variants of this IL-18BP gene, some of which have been shown to act as viral virulence factors. Yaba monkey tumor virus (YMTV) encodes a related family member, 14L, which is similar to the orthopoxvirus IL-18BPs. YMTV 14L was expressed from a baculovirus system and tested for its ability to bind and inhibit IL-18. We found that YMTV 14L bound both human IL-18 (hIL-18) and murine IL-18 with high affinity, at 4.1 nM and 6.5 nM, respectively. YMTV 14L was able to fully sequester hIL-18 but could only partially inhibit the biological activity of hIL-18 as measured by gamma interferon secretion from KG-1 cells. Additionally, 17 hIL-18 point mutants were tested by surface plasmon resonance for their ability to bind to YMTV 14L. Two clusters of hIL-18 surface residues were found to be important for the hIL-18-YMTV 14L interaction, in contrast to results for the Variola virus IL-18BP, which has been shown to primarily interact with a single cluster of three amino acids. The altered binding specificity of YMTV 14L most likely represents an adaptation resulting in increased fitness of the virus and affirms the plasticity of poxviral inhibitor domains that target cytokines like IL-18.


Evidence for the presence of a proton pump of the vacuolar H(+)-ATPase type in the ruffled borders of osteoclasts.
Microsomal membrane vesicles prepared either from chicken medullary bone or isolated osteoclasts were shown to have ATP-dependent H(+)-transport activity. This activity was N-ethylmaleimide-sensitive but resistant to oligomycin and orthovanadate, suggesting a vacuolar-type ATPase. Furthermore, immunological cross-reactivity of 60- and 70-kD osteoclast membrane antigens with Neurospora crassa vacuolar ATPase was observed when analyzed by immunoblotting. Same antibodies labeled only osteoclasts in chicken and rat bone in immunohistochemistry. Immunoelectronmicroscopy localized these antigens in apical membranes of rat osteoclasts and kidney intercalated cells of inner stripe of outer medulla. Pretreatment of animals with parathyroid hormone enhanced the immunoreaction in the apical membranes of osteoclasts. No immunoreaction was seen in osteoclasts when antibodies against gastric H+,K(+)-ATPase were used. These results suggest that osteoclast resorbs bone by secreting protons through vacuolar H(+)-ATPase.


SMAD2 is essential for TGF beta-mediated Th17 cell generation.
TGFβ is the quintessential cytokine of T cell homeostasis. TGFβ signaling is required for the efficient differentiation and maintenance of CD4(+)FOXP3(+) T cells that inhibit immune responses. Conversely, in conjunction with the inflammatory cytokine IL-6, TGFβ promotes Th17 cell differentiation. The mechanism by which TGFβ signals synergize with IL-6 to generate inflammatory versus immunosuppressive T cell subsets is unclear. TGFβ signaling activates receptor SMADs, SMAD2 and SMAD3, which associate with a variety of nuclear factors to regulate gene transcription. Defining relative contributions of distinct SMAD molecules for CD4 T cell differentiation is critical for mapping the versatile intracellular TGFβ-signaling pathways that tailor TGFβ activities to the state of host interaction with pathogens. We show here that SMAD2 is essential for Th17 cell differentiation and that it acts in part by modulating the expression of IL-6R on T cells. Although mice lacking SMAD2 specifically in T cells do not develop spontaneous lymphoproliferative autoimmunity, Smad2-deficient T cells are impaired in their response to TGFβ in vitro and in vivo, and they are more pathogenic than controls when transferred into lymphopenic mice. These results demonstrate that SMAD2 is uniquely essential for TGFβ signaling in CD4(+) T effector cell differentiation.


Arbitrary cylinder color model for the codebook based background subtraction.
The codebook background subtraction approach is widely used in computer vision applications. One of its distinguished features is the cylinder color model used to cope with illumination changes. The performances of this approach depends strongly on the color model. However, we have found this color model is valid only if the spectrum components of the light source change in the same proportion. In fact, this is not true in many practical cases. In these cases, the performances of the approach would be degraded significantly. To tackle this problem, we propose an arbitrary cylinder color model with a highly efficient updating strategy. This model uses cylinders whose axes need not going through the origin, so that the cylinder color model is extended to much more general cases. Experimental results show that, with no loss of real-time performance, the proposed model reduces the wrong classification rate of the cylinder color model by more than fifty percent.


The distribution of randomly recovered X-ray-induced sex-linked genetic effects in Drosophila melanogaster.
Cytogenetic analysis of more than 1500 randomly recovered lethal X chromosomes derived from 2000 and 3000 r X-ray exposures of post-meiotic male germ cells has made possible a plot of the distribution in different regions of the X chromosome of: (1) gene mutations associated with cytologically normal chromosomes, (2) mutations associated with chromosomal rearrangement breakpoints, (3) deficiencies, and (4) rearrangement breakpoints whether or not they are associated with mutations. The distribution of point mutations, vital loci and rearrangement breakpoints in different regions of the X chromosome is not proportional to either the number of bands or the relative DNA content. Further, the density of vital loci (those capable of mutating to a lethal allele) is quite different in some regions as compared to others. For example, vital loci in the 3AB region, which has been thoroughly studied by Judd and others, are at least as numerous as bands; whereas, the 3CD region, equally long, has only two vital loci. Other regions densely populated with vital loci include 1B, 1F-2A, 10A, 11A, and 19EF; sparsely populated regions include 6EF and 10B-10E. It seems reasonable to conclude that the recovered X-ray-induced mutants available for analysis do not represent a random sample of those initially induced in the exposed male germ cells.


Kin-recognition abilities and nepotism as a function of sociality.
Despite widespread interest in kin selection and nepotism, relatively little is known about the perceptual abilities of animals to recognize their relatives. Here I show that a highly nepotistic species, Belding's ground squirrels (Spermophilus beldingi), produces odours from at least two sources that correlate with relatedness ('kin labels'), and that ground squirrels can use these odours to make accurate discriminations among never before encountered ('unfamiliar') kin. Recognition odours appear to vary linearly with relatedness, rather than in an all-or-none fashion, allowing precise estimates of kinship even among distant relatives. Thus S. beldingi are able to recognize their distant kin and male kin, even though they do not treat them preferentially. I also show that a closely related species (S. lateralis) similarly produces kin labels and discriminates among kin, although it shows no evidence of kin-directed behaviour. Thus, contrary to a commonly held assumption, kin favouritism and recognition abilities can evolve independently, depending on variation in the costs and benefits of nepotism for a given species.


Early lactation performance in primiparous and multiparous women in relation to different maternity home practices. A randomised trial in St. Petersburg.
There are not many studies exploring parity differences in early lactation performance and the results obtained are fairly often contradictory. The present study investigated the effect of different maternity home practices in St. Petersburg, Russia, as well as of physiological breast engorgement and maternal mood, on milk production in primi- and multiparous women on day four. The amount of milk was studied in relation to the duration of "nearly exclusive" breastfeeding. 176 mother-infant pairs were randomised into four groups according to an experimental two-factor design taking into account infant location and apparel. Data were recorded in the delivery ward at 25-120 minutes postpartum and later in the maternity ward. Group I infants (n = 37) were placed skin-to-skin in the delivery ward while Group II infants (n = 40) were dressed and placed in their mother's arms. Both groups later roomed-in in the maternity ward. These infants had the possibility of early suckling during two hours postpartum. Group III infants (n = 38) were kept in a cot in the delivery and maternity ward nurseries with no rooming-in. Group IV infants (n = 38) were kept in a cot in a delivery ward nursery and later roomed-in in the maternity ward. Equal numbers per group were either swaddled or clothed. Episodes of early suckling were noted. Number of breastfeeds, amount of milk ingested (recorded on day 4 postpartum) and duration of "nearly exclusive" breastfeeding were recorded. Intensity of breast engorgement was recorded and a Visual Analogue Scale measured daily maternal feelings of being "low/blue". On day four, multiparas had lower milk production than primiparas when they were separated from their infants and breastfeeding according to the prescriptive schedule (7 times a day; Group III). In contrast, there was no difference in milk production between multi- and primiparous mothers in the groups rooming-in and feeding on demand (Groups I, II and IV), although multiparas had higher numbers of feedings than primiparas. In addition during the first three days postpartum, multiparous mothers had higher perception of physiological breast engorgement and lower intensity of feeling "low/blue" than primiparous mothers. Early suckling was shown to positively affect milk production irrespective of parity. Thus Group I and II infants who suckled within the first two hours after birth ingested significantly more milk on day 4 than those who had not (284 and 184 ml respectively, SE = 14 and 27 ml, p = 0.0006).Regression analyses evaluated factors most important for milk production and found in Groups I and II for primiparous women that early suckling, intensity of breast engorgement and number of breastfeeds on day 3 were most important. Intensity of feeling "low/blue" was negatively related to amount of milk ingested. The significant factor for multiparous women was early suckling. Similar results were obtained in Groups III and IV; however, in primiparous mothers, engorgement was the most important factor and in multiparous women it was rooming-in. Amount of milk produced on day 4 was strongly correlated to a duration of "nearly exclusive" breastfeeding (p < 0.0001). The present data show that ward routines influence milk production. As our data suggest that milk production in primi- and multiparous women may be differently influenced or regulated by complex factors, further research is needed.


Systematic position of Pseudocorynosoma and Andracantha (Acanthocephala, Polymorphidae) based on nuclear and mitochondrial gene sequences.
Species of Pseudocorynosoma are North and South American acanthocephalans that use waterfowl as definitive hosts and amphipods as intermediate hosts, whereas species of Andracantha occur in fish-eating birds with a worldwide distribution. Pseudocorynosoma and Andracantha were originally described as Corynosoma (now restricted to endoparasites of marine mammals). Morphologically, Andracantha is distinct from other genera of Polymorphidae in possessing 2 fields of spines on the trunk, whereas Corynosoma and Pseudocorynosoma have a single field. A recent phylogenetic hypothesis based on morphological characters suggested that Andracantha is closely related to Corynosoma, whereas Pseudocorynosoma was of uncertain phylogenetic position within the Polymorphidae. To test the systematic affinities of these 3 genera, we sequenced 2 nuclear genes (SSU and LSU ribosomal DNA) and 1 mitochondrial gene (cytochrome c oxidase subunit 1; cox 1) of species representing Corynosoma, Andracantha, and Pseudocorynosoma and analyzed the data, including available sequences of other polymorphids. Maximum parsimony (MP), maximum likelihood (ML), and Bayesian analyses of the combined (SSU + LSU) sequences and the concatenated data of 3 genes (SSU + LSU + cox 1) placed Andracantha as the sister taxon to Corynosoma with robust support values. All analyses also showed that Pseudocorynosoma is an independent lineage that does not share a common ancestry with Andracantha and Corynosoma. These phylogenetic hypotheses suggest that birds were the ancestral hosts of polymorphids and that the association of Corynosoma with marine mammals represents a subsequent episode of colonization.


Relation of coronary microvascular dysfunction in hypertrophic cardiomyopathy to contractile dysfunction independent from myocardial injury.
We studied the spatial relations among hyperemic myocardial blood flow (hMBF), contractile function, and morphologic tissue alterations in 19 patients with hypertrophic cardiomyopathy (HC). All patients were studied with oxygen-15 water positron emission tomography during rest and adenosine administration to assess myocardial perfusion. Cardiovascular magnetic resonance was performed to derive delayed contrast-enhanced images and to calculate contractile function (E(cc)) with tissue tagging. Eleven healthy subjects underwent similar positron emission tomographic and cardiovascular magnetic resonance scanning protocols and served as a control group. In the HC group, hMBF averaged 2.46 ± 0.91 ml/min/g and mean E(cc) was -14.7 ± 3.4%, which were decreased compared to the control group (3.97 ± 1.48 ml/min/g and -17.7 ± 3.2%, respectively, p <0.001 for the 2 comparisons). Delayed contrast enhancement (DCE) was present only in patients with HC, averaging 6.2 ± 10.3% of left ventricular mass. In the HC group, E(cc) and DCE in the septum (-13.7 ± 3.6% and 10.2 ± 13.6%) significantly differed from the lateral wall (-16.0 ± 2.8% and 2.4 ± 5.9%, p <0.001 for the 2 comparisons). In general, hMBF and E(cc) were decreased in segments displaying DCE compared to nonenhanced segments (p <0.001 for the comparisons). In the HC group, univariate analysis revealed relations of hMBF to E(cc) (r = -0.45, p <0.001) and DCE (r = -0.31, p <0.001). Multivariate analysis revealed that E(cc) was independently related to hMBF (beta -0.37, p <0.001) and DCE (beta 0.28, p <0.001). In conclusion, in HC hMBF is impaired and related to contractile function independent from presence of DCE. When present, DCE reflected a progressed disease state as characterized by an increased perfusion deficit and contractile dysfunction.


The ambidextrous CEO.
Although most managers publicly acknowledge the need to explore new businesses and markets, the claims of established businesses on company resources almost always come first, especially when times are hard. When top teams allow the tension between core and speculative units to play out at lower levels of management, innovation loses out. At best, leaders of core business units dismiss innovation initiatives as irrelevancies. At worst, they see the new businesses as threats to the firm's core identity and values. Many CEOs take a backseat in debates over resources, ceding much of their power to middle managers, and the company ends up as a collection of feudal baronies. This is a recipe for long-term failure, say the authors. Their research of 12 top management teams at major companies suggests that firms thrive only when senior teams lead ambidextrously--when they foster a state of constant creative conflict between the old and the new. Successful CEOs first develop a broad, forward-looking strategic aspiration that sets ambitious targets both for innovation and core business growth. They then hold the tension between innovation unit demands and core business demands at the very top of the organization. And finally they embrace inconsistency, allowing themselves the latitude to pursue multiple and often conflicting agendas.


Bidirectional Text Messaging to Improve Adherence to Recommended Lipid Testing.
Synergies between technology and health care in the United States are accelerating, increasing opportunities to leverage these technologies to improve patient care. This study was a collaboration between an academic study team, a rural primary care clinic, and a local nonprofit informatics company developing tools to improve patient care through population management. Our team created a text messaging management tool, then developed methods for and tested the feasibility of bidirectional text messaging to remind eligible patients about the need for lipid testing. We measured patient response to the text messages, then interviewed 8 patients to explore their text messaging experience. Of the 129 patients the clinic was able to contact by phone, 29.4% had no cell phone or text-messaging capabilities. An additional 20% refused to participate. Two thirds of the 28 patients who participated in the text messaging intervention (67.9%) responded to at least 1 of the up to 3 messages. Seven of 8 interviewed patients had a positive text-messaging experience. Bidirectional text messaging is a feasible and largely acceptable form of communication for test reminders that has the potential to reach large numbers of patients in clinical care.


Factors Affecting the Referral Time to Nephrologists in Patients With Chronic Kidney Disease: A Prospective Cohort Study in Korea.
Timely referral to nephrologists is important for improving clinical outcomes and reducing costs during transition periods. We evaluated the impact of patients' demographic, clinical, and social health characteristics on referral time.A total of 1744 CKD patients who started maintaining dialysis were enrolled in a Korean prospective cohort. The early referral (ER) and late referral group (LR) were defined as patients who were referred to a nephrologist more than or less than 1 year prior to dialysis initiation, respectively.A total of 1088 patients (62.3%) were in the ER, and 656 patients (37.6%) were in the LR. Among the patients in the LR, 398 patients (60.7%) were referred within the 3 months prior to the start of dialysis (ultralate referral group [ULR]). The ER was younger at the time of referral than the LR; however, the ER was older at the start of dialysis. Patients with diabetes or hypertension as the cause of kidney disease were more common in the LR, whereas patients with glomerulonephritis, females, and nonsmokers were more common in the ER. The ER had more well-controlled blood pressure, lower phosphorus levels, and higher hemoglobin levels at the start of dialysis. Congestive heart failure (CHF) was more common in the LR. In the multivariate analysis, male sex (odds ratio [OR] 1.465, 95% confidence interval [CI] 1.034-2.076), underlying kidney disease (diabetes mellitus [OR 1.507, 95% CI 1.057-2.148] and hypertension [OR 1.995, 95% CI 1.305-3.051]), occupation (mechanician [OR 2.975, 95% CI 1.445-6.125], laborer [OR 3.209, 95% CI 1.405-7.327], and farmer [OR 5.147, 95% CI 2.217-11.953]), CHF (OR 2.152, 95% CI 1.543-3.000), and ambulatory status (assisted-walks, OR 2.072, 95% CI 1.381-3.111) were proved as the independent risk factor for late referral.Patients with hypertensive or diabetic kidney disease are referred later than those with glomerulonephritis. Male patients with physically active occupations exhibiting CHF and restricted ambulation were associated with a late referral. Considering the various factors associated with late referral, efforts to increase early referrals should be emphasized, particularly in patients with hypertension, diabetes, or congestive heart failure.


Age-accelerated atherosclerosis correlates with failure to upregulate antioxidant genes.
Excess food intake leads to obesity and diabetes, both of which are well-known independent risk factors for atherosclerosis, and both of which are growing epidemics in an aging population. We hypothesized that aging enhances the metabolic and vascular effects of high fat diet (HFD) and therefore examined the effect of age on atherosclerosis and insulin resistance in lipoprotein receptor knockout (LDLR(-/-)) mice. We found that 12-month-old (middle-aged) LDLR(-/-) mice developed substantially worse metabolic syndrome, diabetes, and atherosclerosis than 3-month-old (young) LDLR(-/-) mice when both were fed HFD for 3 months, despite similar elevations in total cholesterol levels. Microarray analyses were performed to analyze the mechanism responsible for the marked acceleration of atherosclerosis in middle-aged mice. Chow-fed middle-aged mice had greater aortic expression of multiple antioxidant genes than chow-fed young mice, including glutathione peroxidase-1 and -4, catalase, superoxide dismutase-2, and uncoupling protein-2. Aortic expression of these enzymes markedly increased in young mice fed HFD but decreased or only modestly increased in middle-aged mice fed HFD, despite the fact that systemic oxidative stress and vascular reactive oxygen species generation, measured by plasma F2alpha isoprostane concentration (systemic) and dihydroethidium conversion and p47phox expression (vascular), were greater in middle-aged mice fed HFD. Thus, the mechanism for the accelerated vascular injury in older LDLR(-/-) mice was likely the profound inability to mount an antioxidant response. This effect was related to a decrease in vascular expression of 2 key transcriptional pathways regulating the antioxidant response, DJ-1 and forkhead box, subgroup O family (FOXOs). Treatment of middle-aged mice fed HFD with the antioxidant apocynin attenuated atherosclerosis, whereas treatment with the insulin sensitizer rosiglitazone attenuated both metabolic syndrome and atherosclerosis. Both treatments decreased oxidative stress. A novel effect of rosiglitazone was to increase expression of Nrf2 (nuclear factor [erythroid-derived 2]-like 2), a downstream target of DJ-1 contributing to enhanced expression of vascular antioxidant enzymes. This investigation underscores the role of oxidative stress when multiple atherosclerotic risk factors, particularly aging, converge on the vessel wall and emphasizes the need to develop effective strategies to inhibit oxidative stress to protect aging vasculature.