Effect of Vinca rosea extracts in treatment of alloxan diabetes in male albino rats.
Administration of aqueous extracts of V. rosea flower and leaf have been found to regulate the blood sugar level in alloxan diabetic male albino rats. V. rosea therapy not only produced blood glucose homeostasis but also reversed changes in carbohydrate, protein, lipid metabolisms and metabolic and pathologic changes that took place in pancreatic islet cells, liver and kidney following a single dose (150 mg/kg body weight) of alloxan monohydrate. B-cell secretory activity resumed near-normalcy as evidenced by near-normal serum insulin concentration and electron-microscopic study proving that V. rosea manifests its beneficial activity through B-cell rejuvenation, regeneration and stimulation.


Detection of microglial activation in an acute model of neuroinflammation using PET and radiotracers 11C-(R)-PK11195 and 18F-GE-180.
It remains unclear how different translocator protein (TSPO) ligands reflect the spatial extent of astrocyte or microglial activation in various neuroinflammatory conditions. Here, we use a reproducible lipopolysaccharide (LPS)-induced model of acute central nervous system inflammation to compare the binding performance of a new TSPO ligand (18)F-GE-180 with (11)C-(R)-PK11195. Using immunohistochemistry, we also explore the ability of the TSPO ligands to detect activated microglial cells and astrocytes. Lewis rats (n = 30) were microinjected with LPS (1 or 10 μg) or saline (1 μL) into the left striatum. The animals were imaged in vivo at 16 h after the injection using PET radiotracers (18)F-GE-180 or (11)C-(R)-PK11195 (n = 3 in each group) and were killed afterward for autoradiography of the brain. Immunohistochemical assessment of OX-42 and glial fibrillary acidic protein (GFAP) was performed to identify activated microglial cells and reactive astrocytes. In vivo PET imaging revealed an increase in the ipsilateral TSPO binding, compared with binding in the contralateral hemisphere, after the microinjection of 10 μg of LPS. No increase was observed with vehicle. By autoradiography, the TSPO radiotracer binding potential in the injected hemisphere was increased after striatal injection of 1 or 10 μg of LPS. However, the significant increase was observed only when using (18)F-GE-180. The area of CD11b-expressing microglial cells extended beyond that of enhanced GFAP staining and mapped more closely to the extent of (18)F-GE-180 binding than to (11)C-(R)-PK11195 binding. The signal from either PET ligand was significantly increased in regions of increased GFAP immunoreactivity and OX-42 colocalization, meaning that the presence of both activated microglia and astrocytes in a given area leads to increased binding of the TSPO radiotracers. (18)F-GE-180 is able to reveal sites of activated microglia in both gray and white matter. However, the signal is increased by the presence of activated astrocytes. Therefore, (18)F-GE-180 is a promising new fluorinated longer-half-life tracer that reveals the presence of activated microglia in a manner that is superior to (11)C-(R)-PK11195 due to the higher binding potential observed for this ligand.


Uneven dietary development: linking the policies and processes of globalization with the nutrition transition, obesity and diet-related chronic diseases.
In a "nutrition transition", the consumption of foods high in fats and sweeteners is increasing throughout the developing world. The transition, implicated in the rapid rise of obesity and diet-related chronic diseases worldwide, is rooted in the processes of globalization. Globalization affects the nature of agri-food systems, thereby altering the quantity, type, cost and desirability of foods available for consumption. Understanding the links between globalization and the nutrition transition is therefore necessary to help policy makers develop policies, including food policies, for addressing the global burden of chronic disease. While the subject has been much discussed, tracing the specific pathways between globalization and dietary change remains a challenge. To help address this challenge, this paper explores how one of the central mechanisms of globalization, the integration of the global marketplace, is affecting the specific diet patterns. Focusing on middle-income countries, it highlights the importance of three major processes of market integration: (I) production and trade of agricultural goods; (II) foreign direct investment in food processing and retailing; and (III) global food advertising and promotion. The paper reveals how specific policies implemented to advance the globalization agenda account in part for some recent trends in the global diet. Agricultural production and trade policies have enabled more vegetable oil consumption; policies on foreign direct investment have facilitated higher consumption of highly-processed foods, as has global food marketing. These dietary outcomes also reflect the socioeconomic and cultural context in which these policies are operating. An important finding is that the dynamic, competitive forces unleashed as a result of global market integration facilitates not only convergence in consumption habits (as is commonly assumed in the "Coca-Colonization" hypothesis), but adaptation to products targeted at different niche markets. This convergence-divergence duality raises the policy concern that globalization will exacerbate uneven dietary development between rich and poor. As high-income groups in developing countries accrue the benefits of a more dynamic marketplace, lower-income groups may well experience convergence towards poor quality obseogenic diets, as observed in western countries. Global economic policies concerning agriculture, trade, investment and marketing affect what the world eats. They are therefore also global food and health policies. Health policy makers should pay greater attention to these policies in order to address some of the structural causes of obesity and diet-related chronic diseases worldwide, especially among the groups of low socioeconomic status.


Population pharmacokinetics of tenofovir in HIV/HBV co-infected patients.
Tenofovir is an efficacious drug with a long half-life and high activity against both HIV and HBV. However, the pharmacokinetics of tenofovir have not been studied in HIV/HBV co-infected patients. Data from HIV mono-infected patients may not be transferable to HIV/HBV co-infected population because the nature and consequences of the co-infection are different. This study developed a population pharmacokinetic model of tenofovir in patients with HIV/HBV co-infection and identified pathophysiologic factors that affect the pharmacokinetics of the drug. Sparse and intensive blood samples were collected from patients with HIV/HVB coinfection. The population pharmacokinetic model of tenofovir was developed by a nonlinear mixed-effects modeling approach (NONMEM®). A total of 332 tenofovir plasma concentrations from 146 patients were obtained. A two-compartment model best described the pharmacokinetics of tenofovir. Creatinine clearance (estimated by Cockcroft and Gault equation) affected the tenofovir apparent clearance (CL/F). Tenofovir CL/F decreased by 23.5% when concomitantly used with atazanavir/ritonavir. Based on the results from our study, it was shown that the pharmacokinetics of tenofovir in HIV/HBV co-infected patients are comparable to those with HIVmonoinfection. This study confirmed that patients with kidney impairment and the concurrent use of atazanavir/ritonavir will require the dosage of tenofovir to be adjusted to ensure efficacy and prevent unwanted toxicities. The developed model can reliably be used to adjust for the dosage of tenofovir in this population, especially when therapeutic drug monitoring services are unavailable.


Regulatory network analysis of Paneth cell and goblet cell enriched gut organoids using transcriptomics approaches.
The epithelial lining of the small intestine consists of multiple cell types, including Paneth cells and goblet cells, that work in cohort to maintain gut health. 3D in vitro cultures of human primary epithelial cells, called organoids, have become a key model to study the functions of Paneth cells and goblet cells in normal and diseased conditions. Advances in these models include the ability to skew differentiation to particular lineages, providing a useful tool to study cell type specific function/dysfunction in the context of the epithelium. Here, we use comprehensive profiling of mRNA, microRNA and long non-coding RNA expression to confirm that Paneth cell and goblet cell enrichment of murine small intestinal organoids (enteroids) establishes a physiologically accurate model. We employ network analysis to infer the regulatory landscape altered by skewing differentiation, and using knowledge of cell type specific markers, we predict key regulators of cell type specific functions: Cebpa, Jun, Nr1d1 and Rxra specific to Paneth cells, Gfi1b and Myc specific for goblet cells and Ets1, Nr3c1 and Vdr shared between them. Links identified between these regulators and cellular phenotypes of inflammatory bowel disease (IBD) suggest that global regulatory rewiring during or after differentiation of Paneth cells and goblet cells could contribute to IBD aetiology. Future application of cell type enriched enteroids combined with the presented computational workflow can be used to disentangle multifactorial mechanisms of these cell types and propose regulators whose pharmacological targeting could be advantageous in treating IBD patients with Crohn's disease or ulcerative colitis.


Decreased kidney function of unknown cause in Nicaragua: a community-based survey.
End-stage kidney disease overwhelms health services in Central America. We determined prevalences of decreased kidney function in distinct populations in the most affected region of Nicaragua. Cross-sectional survey. Total populations aged 20-60 years of 5 villages in Northwest Nicaragua: mining/subsistence farming (elevation, 100-300 m above sea level), banana/sugarcane (100-300 m), fishing (0-100 m), services (0-100 m), and coffee (200-675 m); 479 men and 617 women (83% response). Village; participant sex, age, and occupation; conventional chronic kidney disease risk factors. Serum creatinine (SCr) values greater than laboratory reference range for sex, estimated glomerular filtration rate <60 mL/min/1.73 m(2), proteinuria stratified in the low (dipstick protein excretion, 30-300 mg/dL) and high (>300 mg/dL) range. Prevalences of abnormal SCr levels: 18% (of all men) and 5% (of all women); in the mining/subsistence farming village, 26% and 7%; banana/sugarcane, 22% and 6%; fishing, 13% and 4%; services, 0% and 1%; and coffee, 7% and 0%. Prevalences of estimated glomerular filtration rate <60 mL/min/1.73 m(2): 14% (of all men) and 3% (of all women); in the listed villages, 19% and 5%, 17% and 4%, 10% and 2%, 0% and 0%, and 7% and 0%, respectively. Proteinuria, predominantly in the low range, affected 14% and 11% of all men and women without marked differences between villages. By occupation, abnormal SCr levels occurred in 31% and 24% of male and female agricultural workers at 100-300 m above sea level, but not at higher altitudes, and also was high in male artisans (43%), construction workers (15%), and miners (14%). In logistic regression models, for the banana/sugarcane and mining/subsistence farming villages, high blood pressure and age were significant predictors of abnormal SCr levels in men, and for mining/subsistence farming, age in women. Causality is not addressed. In some Nicaraguan villages and population segments, men in particular show a high prevalence of decreased kidney function of unknown origin, possibly environmental or occupational.


Surgery-induced insulin resistance in human patients: relation to glucose transport and utilization.
To investigate the underlying molecular mechanisms for surgery-induced insulin resistance in skeletal muscle, six otherwise healthy patients undergoing total hip replacement were studied before, during, and after surgery. Patients were studied under basal conditions and during physiological hyperinsulinemia (60 microU/ml). Biopsies of vastus lateralis muscle were used to measure GLUT-4 translocation, glucose transport, and glycogen synthase activities. Surgery reduced insulin-stimulated glucose disposal (P < 0.05) without altering the insulin-stimulated increase in glucose oxidation or suppression of endogenous glucose production. Preoperatively, insulin infusion increased plasma membrane GLUT-4 in all six subjects (P < 0.05), whereas insulin-stimulated GLUT-4 translocation only occurred in three patients postoperatively (not significant). Moreover, nonoxidative glucose disposal rates and basal levels of glycogen synthase activities in muscle were reduced postoperatively (P < 0.05). These findings demonstrate that peripheral insulin resistance develops immediately postoperatively and that this condition might be associated with perturbations in insulin-stimulated GLUT-4 translocation as well as nonoxidative glucose disposal, presumably at the level of glycogen synthesis.


Use of the hollow fiber assay for the discovery of novel anticancer agents from fungi.
The hollow fiber assay (HFA) is a drug discovery tool to aid investigators in the prioritization of lead compounds identified by in vitro testing for further development in animal models of disease. In the HFA, cells are cultured in hollow fibers containing pores of a diameter (500 kDa) large enough for proteins and other macromolecules to enter, but too small for the cells to escape. The fibers are filled with cells, sealed and placed in the peritoneal cavity of immunodeficient mice. The mice undergo a predetermined treatment regimen after which the fibers are retrieved and the cells evaluated for activity of a target relevant to the disease modeled. The HFA combines advantages of both in vitro and in vivo assay systems. It uses the same cell lines used in culture systems, is a rapid assay, and requires fewer animals and less test substance than conventional xenograft systems. Like traditional in vivo assays, the test substance is evaluated in a live animal, which affords an initial assessment of associated toxicity and pharmacokinetic properties of the test substance.


Effect of synaptic transmission on viral fitness in HIV infection.
HIV can spread through its target cell population either via cell-free transmission, or by cell-to-cell transmission, presumably through virological synapses. Synaptic transmission entails the transfer of tens to hundreds of viruses per synapse, a fraction of which successfully integrate into the target cell genome. It is currently not understood how synaptic transmission affects viral fitness. Using a mathematical model, we investigate how different synaptic transmission strategies, defined by the number of viruses passed per synapse, influence the basic reproductive ratio of the virus, R(0), and virus load. In the most basic scenario, the model suggests that R(0) is maximized if a single virus particle is transferred per synapse. R(0) decreases and the infection eventually cannot be maintained for larger numbers of transferred viruses, because multiple infection of the same cell wastes viruses that could otherwise enter uninfected cells. To explain the relatively large number of HIV copies transferred per synapse, we consider additional biological assumptions under which an intermediate number of viruses transferred per synapse could maximize R(0). These include an increased burst size in multiply infected cells, the saturation of anti-viral factors upon infection of cells, and rate limiting steps during the process of synapse formation.


[Clinical trials for treatment of primary hyperlipidemia by using acupuncture in combination with Lipitor].
To observe the clinical effect of acupuncture therapy combined with Lipitor in the treatment of primary hyperlipidemia (spleen deficiency and food stagnation type). Sixty primary hyperlipidemia patients (spleen deficiency and food stagnation type) were equally randomized into medication group and acupuncture plus medication group. Patients of both groups were treated by oral administration of Lipitor (20 mg/tablet, one tablet per day) for 6 weeks. Manual acupuncture stimulation was applied to Baihui (GV 20), Zhongwan (CV 12), and bilateral Zusanli (ST 36), Sanyinjiao (SP 6), Yin-lingquan (SP 9) and Fenglong (ST 40) for 40 min, twice daily for 6 weeks except the weekends. Serum total cholesterol (TC), triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C) were detected by using a full-automatic biochemistry analyzer before and after the treatment. The therapeutic effect was assessed according to the standards described in "Guide Principles for Clinical Researches of New Chinese Herbal Drugs". After the treatment, the levels of serum TC, TG of the two groups were significantly decreased in comparison with pre-treatment in the same one group (P<0.05), and the therapeutic effect of the acupuncture+medication group was significantly superior to that of simple medication group in lowering serum TC, TG and LDL-C levels and heightening HDL-C levels (P<0.05). Of the two 30 cases in the medication and acupuncture+medication groups, 2 (6.7%) and 7 (23.3%) were basically controlled in their blood-lipid levels, 10 (33.3%) and 15 (50.0%) had a marked improvement, 10 (33.3%) and 6 (20.0%) were improved, and 8 (26.7%) and 2 (6.7%) were invalid, with the effective rates being 73.3% and 93.3%, respectively. Acupuncture combined with administration of Lipitor is effective in improving primary hyperlipidemia in patients, which is superior to administration of simple Lipitor.


Specificity and inhibitory activity of antibodies to Plasmodium falciparum aldolase.
The multiplication of Plasmodium falciparum within RBC is energy-dependent and the glucose consumption of infected RBC is increased more than 50 times over the consumption of normal RBC. High levels of glycolytic enzymes such as fructose-1,6-diphosphate aldolase (p41) have been detected in infected RBC. Expression of the cloned aldolase gene of P. falciparum in Escherichia coli resulted in an enzymatically active polypeptide with a high sp. act. and the recombinant p41 aldolase was used for enzymatic and immunologic studies reported here. The presence of antibodies against p41 in the sera of human adults partially immune to malaria and immunization experiments in monkeys suggest that p41 is implicated in protective immune response against the parasite. Therefore, we analyzed the capacity of various antisera to inhibit P. falciparum aldolase activity. It was found that anti-p41 antibodies raised in mice, rabbits, and monkeys inhibited very efficiently aldolase activity in vitro up to dilutions higher than 10(-3). In contrast none of the human sera with high levels of anti-p41 antibodies were able to inhibit parasite aldolase activity even at a dilution of 1/2. The inability of human antisera to neutralize parasite aldolase is not related to antibody titers but is probably related to the specificity of the human antibodies. This finding is discussed in relation to homology of structure of P. falciparum and mammalian aldolase and to a possible mechanism of parasite adaptation and survival in its natural host.


Engineering of an epoxide hydrolase for efficient bioresolution of bulky pharmaco substrates.
Optically pure epoxides are essential chiral precursors for the production of (S)-propranolol, (S)-alprenolol, and other β-adrenergic receptor blocking drugs. Although the enzymatic production of these bulky epoxides has proven difficult, here we report a method to effectively improve the activity of BmEH, an epoxide hydrolase from Bacillus megaterium ECU1001 toward α-naphthyl glycidyl ether, the precursor of (S)-propranolol, by eliminating the steric hindrance near the potential product-release site. Using X-ray crystallography, mass spectrum, and molecular dynamics calculations, we have identified an active tunnel for substrate access and product release of this enzyme. The crystal structures revealed that there is an independent product-release site in BmEH that was not included in other reported epoxide hydrolase structures. By alanine scanning, two mutants, F128A and M145A, targeted to expand the potential product-release site displayed 42 and 25 times higher activities toward α-naphthyl glycidyl ether than the wild-type enzyme, respectively. These results show great promise for structure-based rational design in improving the catalytic efficiency of industrial enzymes for bulky substrates.


Does Time Fly When You Are Having Fun? A Day Reconstruction Method Analysis.
Duration-based measures of happiness from retrospectively constructed daily diaries are gaining in popularity in population-based studies of the hedonic experience. Yet experimental evidence suggests that perceptions of duration - how long an event lasts - are influenced by individuals' emotional experiences during the event. An important remaining question is whether observational measures of duration outside the laboratory setting, where the events under study are engaged in voluntarily, may be similarly affected, and if so, for which emotions are duration biases a potential concern. This study assesses how duration and emotions co-vary using retrospective, 24-hour diaries from a national sample of older couples. Data are from the Disability and Use of Time (DUST) supplement to the nationally representative U.S. Panel Study of Income Dynamics. We find that experienced wellbeing (positive, negative emotion) and activity duration are inversely associated. Specific positive emotions (happy, calm) are not associated with duration, but all measures of negative wellbeing considered here (frustrated, worried, sad, tired, and pain) have positive correlations (ranging from 0.04 to 0.08; p<.05). However, only frustration remains correlated with duration after controlling for respondent, activity and day-related characteristics (0.06, p<.01). The correlation translates into a potentially upward biased estimate of duration of up to 10 minutes (20%) for very frustrating activities. We conclude that estimates of time spent feeling happy yesterday generated from diary data are unlikely to be biased but more research is needed on the link between duration estimation and feelings of frustration.


Fronto-Striatal Glutamate in Autism Spectrum Disorder and Obsessive Compulsive Disorder.
Autism spectrum disorders (ASDs) and obsessive compulsive disorder (OCD) are often comorbid with the overlap based on compulsive behaviors. Although previous studies suggest glutamatergic deficits in fronto-striatal brain areas in both disorders, this is the first study to directly compare the glutamate concentrations across the two disorders with those in healthy control participants using both categorical and dimensional approaches. In the current multi-center study (four centers), we used proton magnetic resonance spectroscopy in 51 children with ASD, 29 with OCD, and 53 healthy controls (aged 8-13 years) to investigate glutamate (Glu) concentrations in two regions of the fronto-striatal circuit: midline anterior cingulate cortex (ACC) and left dorsal striatum. Spectra were processed with Linear Combination Model. Group comparisons were performed with one-way analyses of variance including sex, medication use, and scanner site as covariates. In addition, a dimensional analysis was performed, linking glutamate with a continuous measure of compulsivity across disorders. There was a main group effect for ACC glutamate (p=0.019). Contrast analyses showed increased glutamate both in children with ASD and OCD compared with controls (p=0.007), but no differences between the two disorders (p=0.770). Dimensional analyses revealed a positive correlation between compulsive behavior (measured with the Repetitive Behavior Scale) and ACC glutamate (rho=0.24, p=0.03). These findings were robust across sites. No differences were found in the striatum. The current findings confirm overlap between ASD and OCD in terms of glutamate involvement. Glutamate concentration in ACC seems to be associated with the severity of compulsive behavior.


Prenatal exposure to air pollution as a potential risk factor for autism and ADHD.
Genetic and environmental factors both contribute to the development of Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD). One suggested environmental risk factor for ASD and ADHD is air pollution, but knowledge of its effects, especially in low-exposure areas, are limited. Here, we investigate risks for ASD and ADHD associated with prenatal exposure to air pollution in an area with air pollution levels generally well below World Health Organization (WHO) air quality guidelines. We used an epidemiological database (MAPSS) consisting of virtually all (99%) children born between 1999 and 2009 (48,571 births) in the study area, in southern Sweden. MAPSS consists of data on modelled nitrogen oxide (NOx) levels derived from a Gaussian dispersion model; maternal residency during pregnancy; perinatal factors collected from a regional birth registry; and socio-economic factors extracted from Statistics Sweden. All ASD and ADHD diagnoses in our data were undertaken at the Malmö and Lund Departments of Child and Adolescent Psychiatry, using standardized diagnostic instruments. We used logistic regression analyses to obtain estimates of the risk of developing ASD and ADHD associated with different air pollution levels, with adjustments for potential perinatal and socio-economic confounders. In this longitudinal cohort study, we found associations between air pollution exposure during the prenatal period and and the risk of developing ASD. For example, an adjusted Odds Ratio (OR) of 1.40 and its 95% Confidence Interval (CI) (95% CI: 1.02-1.93) were found when comparing the fourth with the first quartile of NOx exposure. We did not find similar associations on the risk of developing ADHD. This study contributes to the growing evidence of a link between prenatal exposure to air pollution and autism spectrum disorders, suggesting that prenatal exposure even below current WHO air quality guidelines may increase the risk of autism spectrum disorders.


Double-beam two-channel wavelength-modulated reflectometer.
A double-beam wavelength-modulated reflectometer utilizing a single detector and without a reflectivity reference has been described. Separate electronic channels are used for the two wavelengths at which the reflectometer alternatively operates. The gain of one of the channels is controlled by feedback to eliminate the instrumental background. The derivative and conventional reflectivity are measured simultaneously. The influence of the photomultiplier dark current and scattered light on the accuracy and of some design parameters on the SNR have been evaluated. The system has been checked by measuring the derivative and conventional reflectivity spectrum of GaAs.


Triflavin potentiates the antiplatelet activity of platelet activating factor receptor antagonist on activated neutrophil-induced platelet aggregation.
In this study, specific platelet activating factor (PAF) receptor antagonist ginkgolide B (BN52021) was tested for its antiplatelet activity in zymosan activated polymorphonuclear neutrophil-induced platelet aggregation. Triflavin was also tested for its antiplatelet activity compared with PAF receptor antagonist. Triflavin, an Arg-Gly-Asp-containing disintegrin purified from venom peptide inhibited platelet aggregation by interfering with the interaction of fibrinogen with the glycoprotein IIb/IIIa complex. Furthermore, we also report an efficient high resolution method for quantitative analysis of PAF using high-performance capillary electrophoresis (HPCE). The supernatant of polymorphonuclear neutrophils after their activation by opsonized zymosan induces the aggregation of washed rabbit platelets. In rabbit platelets, BN52021 (100-1000 microM) only partially inhibited activated polymorphonuclear neutrophil-induced platelet aggregation, and its maximal inhibition was estimated to be about 79%. Triflavin also partially inhibited platelet aggregation about 82% induced by activated polymorphonuclear neutrophils. Furthermore, after treatment with a combination of triflavin (0.26 microM) with various concentrations of BN52021 (4-1000 microM), the inhibitory effect of platelet aggregation was almost completely. This inhibition was greater than that produced by the individual drugs alone. These results indicate that a combination of glycoprotein IIb/IIIa complex and PAF receptor antagonist could completely inhibit activated polymorphonuclear neutrophil-induced platelet aggregation. In addition, the amount of PAF released from zymosan (6 mg/ml)-activated polymorphonuclear neutrophils was accurately calculated about 11.8+/-1.5 ng/10(6) cells, and did not further increase even at a high concentration of zymosan (10 mg/ml). These results suggest that PAF play a major role in the interaction between platelets and polymorphonuclear neutrophils. This interaction may be important in the pathogenesis of thrombosis and inflammatory diseases. Our present findings support the hypothesis that combination therapy with glycoprotein IIb/IIIa complex antagonists and PAF receptor antagonists may represent a new approach to the treatment of ischemic disorders.


Model discrimination for Ca2+ -dependent regulation of myosin light chain kinase in smooth muscle contraction.
Excitation-contraction coupling in smooth muscle is mediated by the Ca2+ - and calmodulin-dependent regulation of myosin light chain kinase. The precise mechanism of this regulation remains controversial, and several mathematical models have been proposed for the interaction of the three species. These models have previously been analyzed at steady state primarily by numerical simulation of differential equations, for which parameter values must be estimated from data. Here, we use the linear framework for timescale separation to demonstrate that models of this general kind can be solved analytically for an equilibrium steady state, without having to determine parameter values. This analysis leads to parameter-independent methods for discriminating between the models, for which we propose experiments that could be performed with existing methods.


Association between quality domains and health care spending across physician networks.
One of the more fundamental health policy questions is the relationship between health care quality and spending. A better understanding of these relationships is needed to inform health systems interventions aimed at increasing quality and efficiency of care. We measured 65 validated quality indicators (QI) across Ontario physician networks. QIs were aggregated into domains representing six dimensions of care: screening and prevention, evidence-based medications, hospital-community transitions (7-day post-discharge visit with a primary care physician; 30-day post-discharge visit with a primary care physician and specialist), potentially avoidable hospitalizations and emergency department (ED) visits, potentially avoidable readmissions and unplanned returns to the ED, and poor cancer end of life care. Each domain rate was computed as a weighted average of QI rates, weighting by network population at risk. We also measured overall and sector-specific per capita healthcare network spending. We evaluated the associations between domain rates, and between domain rates and spending using weighted correlations, weighting by network population at risk, using an ecological design. All indicators were measured using Ontario health administrative databases. Large variations were seen in timely hospital-community transitions and potentially avoidable hospitalizations. Networks with timely hospital-community transitions had lower rates of avoidable admissions and readmissions (r = -0.89, -0.58, respectively). Higher physician spending, especially outpatient primary care spending, was associated with lower rates of avoidable hospitalizations (r = -0.83) and higher rates of timely hospital-community transitions (r = 0.81) and moderately associated with lower readmission rates (r = -0.46). Investment in effective primary care services may help reduce burden on the acute care sector and associated expenditures.


Incidence and mechanism of bradycardia during apnoea in preterm infants.
Bradycardia occurred during 363 of 1520 apnoeas of 10 seconds' duration recorded in 28 preterm infants. The incidence increased with increasing duration of apnoea (10% of 10-14 seconds, 34% of 15-20 seconds, and 75% of greater than 20 seconds, p less than 0.001). This was similar for each type of apnoea--central, mixed, and obstructive. During 133 apnoeas in five infants the time from the start of the apnoea to the onset in the fall in oxygen saturation (mean 6.9 seconds) was significantly related to the onset of the fall in heart rate (mean 9.3 seconds) (r = 0.67, p less than 0.001). Recovery in heart rate coincided with resumption of air flow rather than breathing efforts and preceded the recovery in oxygen saturation. These results suggest that bradycardia occurs during apnoea as a response to falling oxygen saturation, probably through a peripheral chemoreceptor reflex that is manifest when breathing efforts are absent or ineffective.


Mapping and comparing bacterial microbiota in the sinonasal cavity of healthy, allergic rhinitis, and chronic rhinosinusitis subjects.
The role of microbiota in sinonasal inflammation can be further understood by targeted sampling of healthy and diseased subjects. We compared the microbiota of the middle meatus (MM) and inferior meatus (IM) in healthy, allergic rhinitis (AR), and chronic rhinosinusitis (CRS) subjects to characterize intrasubject, intersubject, and intergroup differences. Subjects were recruited in the office, and characterized into healthy, AR, and CRS groups. Endoscopically-guided swab samples were obtained from the MM and IM bilaterally. Bacterial microbiota were characterized by sequencing the V3-V4 region of the 16S ribosomal RNA (rRNA) gene. Intersubject microbiome analyses were conducted in 65 subjects: 8 healthy, 11 AR, and 46 CRS (25 CRS with nasal polyps [CRSwNP]; 21 CRS without nasal polyps [CRSsNP]). Intrasubject analyses were conducted for 48 individuals (4 controls, 11 AR, 8 CRSwNP, and 15 CRSwNP). There was considerable intersubject microbiota variability, but intrasubject profiles were similar (p = 0.001, nonparametric t test). Intrasubject bacterial diversity was significantly reduced in MM of CRSsNP subjects compared to IM samples (p = 0.022, nonparametric t test). CRSsNP MM samples were enriched in Streptococcus, Haemophilus, and Fusobacterium spp. but exhibited loss of diversity compared to healthy, CRSwNP, and AR subject-samples (p < 0.05; nonparametric t test). CRSwNP patients were enriched in Staphylococcus, Alloiococcus, and Corynebacterium spp. This study presents the sinonasal microbiome profile in one of the larger populations of non-CRS and CRS subjects, and is the first office-based cohort in the literature. In contrast to healthy, AR, and CRSwNP subjects, CRSsNP MM samples exhibited decreased microbiome diversity and anaerobic enrichment. CRSsNP MM samples had reduced diversity compared to same-subject IM samples, a novel finding.


Optical resonances in periodic surface arrays of metallic patches.
The transmission of light along the surface normal through an air-quartz-glass interface covered with a periodic array of thin, rectangular gold patches has been studied over the visible to infrared range. The various structures that are observed can be qualitatively understood as arising from standing-wave resonances set by the size and surroundings of the metal patches. A method-of-moments calculational scheme provides simulations in good quantitative agreement with the data. It is shown how the standing-wave picture provides a useful conceptual framework to understand and exploit such systems.


Depression and associated physical diseases and symptoms.
Depression can occur in association with virtually all the other psychiatric and physical diagnoses. Physical illness increases the risk of developing severe depressive illness. There are two broadly different mechanisms. The most obvious has a psychological or cognitive mechanism. Thus, the illness may provide the life event or chronic difficulty that triggers a depressive episode in a vulnerable individual. Secondly, more specific associations appear to exist between depression and particular physical disorders. These may turn out to be of particular etiological interest. The best examples are probably stroke and cardiovascular disease. Finally, major depression, but especially minor depression, dysthymia, and depressive symptoms merge with other manifestations of human distress with which patients present to their doctors. Such somatic presentations test the conventional distinction between physical and mental disorder and are a perennial source of controversy.


Deciphering fungal dimorphism: Farnesol's unanswered questions.
Candida albicans excretes E,E-farnesol as a virulence factor and quorum sensing molecule that prevents the yeast to hyphal conversion. Polke et al. (2016) identified eed1Δ/Δ as the first farnesol hypersensitive mutant of C. albicans. eed1Δ/Δ also excretes 10X more farnesol and while able to form hyphae, it cannot maintain hyphae. This mutant enables new research into unanswered questions, including the existence of potential farnesol receptors and transporters, regulation of farnesol synthesis, and relationships among farnesol, germ tube formation and hyphal maintenance. The eed1 farnesol hypersensitivity can be explained by higher internal concentrations of farnesol or lower thresholds for response. One possibility invokes misexpression of a transporter. Saccharomyces cerevisiae and C. albicans have transporters for farnesylated peptides, like the a-factor pheromone, which could potentially also transport farnesol for virulence and quorum sensing. Significantly, these transporters are repressed in MTLa/MTLα C. albicans. An evolutionary pressure for C. albicans to become diploid could derive from its use of farnesol. Alternatively, maintenance of hyphal growth may increase the farnesol response threshold. Finally, Dpp1p, Dpp2p and Dpp3p are non-specific pyrophosphatases responsible for farnesol synthesis. Changes in expression of these enzymes do not explain differences in farnesol levels implicating involvement of additional factors like a scaffolding molecule.


Reconstruction of a replication-competent ancestral murine endogenous retrovirus-L.
About 10% of the mouse genome is composed of endogenous retroviruses (ERVs) that represent a molecular fossil record of past retroviral infections. One such retrovirus, murine ERV-L (MuERV-L) is an env-deficient ERV that has undergone episodic proliferation, with the most recent amplification occurring ~ 2 million years ago. MuERV-L related sequences have been co-opted by mice for antiretroviral defense, and possibly as promoters for some genes that regulate totipotency in early mouse embryos. However, MuERV-L sequences present in modern mouse genomes have not been observed to replicate. Here, we describe the reconstruction of an ancestral MuERV-L (ancML) sequence through paleovirological analyses of MuERV-L elements in the modern mouse genome. The resulting MuERV-L (ancML) sequence was synthesized and a reporter gene embedded. The reconstructed MuERV-L (ancML) could replicate in a manner that is dependent on reverse transcription and generated de novo integrants. Notably, MuERV-L (ancML) exhibited a narrow host range. Interferon-α could reduce MuERV-L (ancML) replication, suggesting the existence of interferon-inducible genes that could inhibit MuERV-L replication. While mouse APOBEC3 was able to restrict the replication of MuERV-L (ancML), inspection of endogenous MuERV-L sequences suggested that the impact of APOBEC3 mediated hypermutation on MuERV-L has been minimal. The reconstruction of an ancestral MuERV-L sequence highlights the potential for the retroviral fossil record to illuminate ancient events and enable studies of the impact of retroviral elements on animal evolution.


Prevention of Syncope Trial (POST): a randomized clinical trial of beta blockers in the prevention of vasovagal syncope; rationale and study design.
Few therapies for vasovagal syncope have been proven effective. A large, placebo-controlled clinical trial of beta-blockers is needed. The Prevention of Syncope Trial (POST) is a multicentre, randomized, placebo-controlled, study of metoprolol in the prevention of vasovagal syncope. The primary hypothesis is that beta-blockers will increase the time to the first recurrence of syncope when compared with placebo. Patients will be randomized 1:1 to receive metoprolol or placebo, and followed for 1 year. The primary endpoint is the time to first syncope recurrence, and secondary endpoints include syncope frequency, presyncope, and quality of life. Patients are eligible if they have a positive tilt test and 3 syncopal spells preceding the tilt test. They are excluded if they have seizures or other causes of syncope; important heart disease; a contraindication to or need for beta blockers; a permanent pacemaker; a major noncardiovascular disease; or previous use of beta blockers at a dose greater than the equivalent of metoprolol 25mg twice daily for the purpose of suppressing vasovagal syncope. We assume a 40% risk of syncope in the control arm, an absolute reduction of 20% by metoprolol, and a dropout of 20%. Entry of 220 patients will result in an 80% chance of reaching a positive conclusion about beta-blocker therapy with 2p=0.05.


Extended release quetiapine fumarate monotherapy in major depressive disorder: a placebo- and duloxetine-controlled study.
To evaluate the efficacy and tolerability of once-daily extended release quetiapine fumarate (quetiapine XR) as monotherapy treatment for major depressive disorder (MDD). This 8-week (6-week active-treatment, randomized phase; 2-week posttreatment drug-discontinuation/tapering phase), multicenter, double-blind, randomized, parallel-group, placebo- and active-controlled, phase 3 study was conducted between April 2006 and May 2007. In total, 612 patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)-defined MDD were randomly assigned to quetiapine XR 150 mg/day or 300 mg/day, duloxetine 60 mg/day (active control), or placebo. The primary endpoint was the change from baseline to week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) total score. At week 6, both doses of quetiapine XR (p < .001) and duloxetine (p < .01) significantly reduced mean MADRS total score versus placebo. A significant reduction was seen at week 1 with quetiapine XR 150 mg/day and 300 mg/day versus placebo (p < .01), but not with duloxetine. Response rates (>or= 50% reduction in MADRS total score) at week 6 were significantly higher for both doses of quetiapine XR (p < .01) and duloxetine (p < .05) versus placebo. Remission rates (MADRS score <or= 8) were significantly higher for quetiapine XR 300 mg/day and duloxetine versus placebo (p < .05), but not for quetiapine XR 150 mg/day. Hamilton Rating Scale for Depression, Hamilton Rating Scale for Anxiety, and Clinical Global Impressions-Severity of Illness total scores and the proportion of patients with Clinical Global Impressions-Improvement scores of 1 or 2 ("much/very much improved") were significantly improved with both doses of quetiapine XR and duloxetine versus placebo. The most common adverse events reported were dry mouth, sedation, and somnolence for quetiapine XR and nausea, headache, dizziness, and dry mouth for duloxetine. Quetiapine XR monotherapy (150 mg/day and 300 mg/day) is effective, with safety and tolerability consistent with the known profile of quetiapine XR, in the treatment of patients with MDD, with onset of symptom improvement demonstrated at week 1. clinicaltrials.gov Identifier: NCT00321490.


All-optically reconfigurable and tunable fiber surface grating for in-fiber devices: a wideband tunable filter.
A fiber surface grating (FSG) formed from a photosensitive liquid crystal hybrid (PLCH) film overlaid on a side-polished fiber (SPF) is studied and has been experimentally shown to be able to function as an all-optically reconfigurable and tunable fiber device. The device is all-optically configured to be a short period fiber surface grating (SPFSG) when a phase mask is used, and then reconfigured to be a long period FSG (LPFSG) when an amplitude mask is used. Experimental results show that both the short and long period FSGs can function as an optically tunable band-rejection filter and have different performances with different pump power and different configured period of the FSG. When configured as a SPFSG, the device can achieve a high extinction ratio (ER) of 21.5dB and a wideband tunability of 31nm are achieved. When configured as a LPFSG, the device can achieve an even higher ER of 23.4dB and a wider tunable bandwidth of 60nm. Besides these tunable performances of the device, its full width at half maximum (FWHM) can also be optically tuned. The reconfigurability and tunability of the fiber device open up possibilities for other all-optically programmable and tunable fiber devices.


High-dimensional cytometric analysis of colorectal cancer reveals novel mediators of antitumour immunity.
A comprehensive understanding of anticancer immune responses is paramount for the optimal application and development of cancer immunotherapies. We unravelled local and systemic immune profiles in patients with colorectal cancer (CRC) by high-dimensional analysis to provide an unbiased characterisation of the immune contexture of CRC. Thirty-six immune cell markers were simultaneously assessed at the single-cell level by mass cytometry in 35 CRC tissues, 26 tumour-associated lymph nodes, 17 colorectal healthy mucosa and 19 peripheral blood samples from 31 patients with CRC. Additionally, functional, transcriptional and spatial analyses of tumour-infiltrating lymphocytes were performed by flow cytometry, single-cell RNA-sequencing and multispectral immunofluorescence. We discovered that a previously unappreciated innate lymphocyte population (Lin-CD7+CD127-CD56+CD45RO+) was enriched in CRC tissues and displayed cytotoxic activity. This subset demonstrated a tissue-resident (CD103+CD69+) phenotype and was most abundant in immunogenic mismatch repair (MMR)-deficient CRCs. Their presence in tumours was correlated with the infiltration of tumour-resident cytotoxic, helper and γδ T cells with highly similar activated (HLA-DR+CD38+PD-1+) phenotypes. Remarkably, activated γδ T cells were almost exclusively found in MMR-deficient cancers. Non-activated counterparts of tumour-resident cytotoxic and γδ T cells were present in CRC and healthy mucosa tissues, but not in lymph nodes, with the exception of tumour-positive lymph nodes. This work provides a blueprint for the understanding of the heterogeneous and intricate immune landscape of CRC, including the identification of previously unappreciated immune cell subsets. The concomitant presence of tumour-resident innate and adaptive immune cell populations suggests a multitargeted exploitation of their antitumour properties in a therapeutic setting.


Current status of hepatocellular carcinoma in Japan.
Approximately 32,000 patients die of primary liver cancer each year in Japan. The annual number of deaths from primary liver cancer in Japan ranks second only to that in China in the world. In recent years, there has been a gradual trend towards decrease in the number of liver cancer patients from its peak in Japan, and this trend is expected to also continue in the future. The main reason for this decreasing trend was the establishment of screening of transfusion products for hepatitis B and hepatitis C viruses, which prevents transfusion-related transmission of the viral infection. Most patients with hepatocellular carcinoma (HCC) in Japan have underlying viral hepatitis, with hepatitis C accounting for about two-third of all the patients and hepatitis B accounting for about 15%. Regular screening of patients with viral hepatitis infection makes it possible to diagnose HCC early, and also enables effective loco-regional treatment, such as surgical resection, local ablative therapy and transcatheter arterial chemoembolization (TACE). However, HCC recurrence is encountered frequently even after these potentially effective treatments. After numerous loco-regional treatments for recurrent HCC, chemotherapy is administered for patients with highly advanced HCC. Among the modalities of chemotherapy, hepatic arterial infusion chemotherapy (HAIC) is employed more commonly than systemic chemotherapy, although no survival advantage has ever been demonstrated. Randomized controlled studies are currently under way to clarify the survival benefit of HAIC. Also, various novel systemic chemotherapeutic agents are currently under development in Japan, and further improvements in the treatment outcomes are expected.


A Phase I study with an anti-CD30 ricin A-chain immunotoxin (Ki-4.dgA) in patients with refractory CD30+ Hodgkin's and non-Hodgkin's lymphoma.
Ki-4.dgA is an anti-CD30 immunotoxin (IT) constructed by coupling the monoclonal antibody Ki-4 via a sterically hindered disulfide linker to deglycosylated ricin A-chain. This IT was efficacious in vitro and in SCID mice with disseminated human Hodgkin's lymphoma. Accordingly, a Phase I trial in patients (pts) with Hodgkin's lymphoma was designed. The objectives of this Phase I trial were to determine the maximum tolerated dose, the dose-limiting toxicities, pharmacokinetics, and antitumor activity. Seventeen pts with relapsed CD30+ lymphoma were treated with escalating doses (5, 7.5, or 10 mg/m(2)/cycle) of the IT as four bolus infusions on days 1, 3, 5, and 7 for one to three cycles. All of the pts had progressive disease and were heavily pretreated. Nine had primary progressive disease and 14 had advanced disease with massive tumor burdens. The mean age was 35 years (24-52 years). Peak serum concentrations of the intact IT varied from 0.23 to 1.1 microg/ml. Side effects and dose-limiting toxicities were related to vascular leak syndrome, i.e., decreases in serum albumin, edema, weight gain, hypotension, tachycardia, myalgia, and weakness. The maximum tolerated dose was 5 mg/m(2). Seven of 17 (40%) pts made human antiricin antibodies (> or =1.0 microg/ml), and 1 pt developed human antimouse antibodies (> or =1.0 microg/ml). Clinical response in the 15 evaluable pts included 1 partial remission, 1 minor response, and 2 stable diseases. In conclusion, the IT was less well tolerated than other ITs of this type. This might be because of the low number of CD30+ peripheral blood mononuclear cells, and in part because of binding of the IT to soluble CD30 antigen and the resulting circulation of IT/sCD30 complexes.


Predicting biliary complications in right lobe liver transplant recipients according to distance between donor's bile duct and corresponding hepatic artery.
To retrospectively determine whether biliary complications in recipients of living-donor right lobe liver grafts can be predicted at pretransplantation donor computed tomography (CT). The human research committee approved this study. The requirement for informed consent was waived. Multi-detector row CT cholangiography and CT angiography were performed in 44 consecutive right lobe liver donors (25 men, 19 women; mean age, 37 years). When CT cholangiography in the donor demonstrated the right biliary anatomy (conventional or variant), the shortest distance between the right main (or second-order) hepatic artery and the corresponding right main (or second-order) bile duct was measured and compared with posttransplantation biliary complications in the transplant recipient by using generalized estimating equations. In 22 transplant recipients with one right main duct-to-common duct anastomosis (ie, conventional donor anatomy), the distance between the donor's right main bile duct and hepatic artery generally was small (mean distance, 3.8 mm; range, 1-14 mm) and unrelated (P=.46) to biliary complications (n=6). In 22 recipients who required two second-order right duct anastomoses (ie, with variant donor anatomy), the distance between the donor's second-order duct and corresponding hepatic artery was more variable (mean distance, 6.6 mm; range, 1-32.5 mm), and biliary complications were significantly more common when this distance was 10 mm or greater (in eight of 13 ducts with conventional anatomy and four of 31 ducts with variant anatomy, P<.05). Right lobe liver graft recipients who have variant right biliary anatomy and a second-order bile duct 10 mm or farther from the corresponding hepatic artery are at high risk for biliary complications, possibly because of a predisposition to ischemic injury.


Evaluation of a preclinical, educational and skills-training program to improve students' use of blood and body fluid precautions: one-year follow-up.
Little is known about long-term improvements in medical students' knowledge, attitudes, and use of blood and body fluid precautions following preclinical training. We evaluated an educational and skills-training program emphasizing double gloving for high-risk surgical procedures. Baseline surveys measuring knowledge, attitudes, and readiness to use specific precautions were completed by second-year (experimental) students before skills training and by third-year students (control) after their first clinical year. Follow-up surveys were completed 1 year later. Use of double gloves and protective eyewear during surgery clerkships was observed at baseline and follow-up. Of 149 students returning both surveys, the experimental group (n = 91) showed improvements in attitudes toward double gloving (P = 0.038) and use of double gloves during surgery at follow-up (relative risk = 1.95, 95% confidence interval = 1.06, 3.59). They expressed better attitudes toward (P = 0.003) and greater readiness to use (P = 0. 020) double gloves compared with controls at follow-up. They expressed better attitudes toward (P = 0.002) and greater readiness to use (P = 0.001) double gloves compared with controls when each had completed their first clinical year. The intervention was associated with improved attitudes toward and use of double gloves during surgery. The experimental group also expressed better attitudes and readiness to use double gloves compared with controls at follow-up.


Ab initio investigation of dissolution mechanisms in aluminosilicate minerals.
The reactions of aluminosilicate clusters with water are investigated using ab initio calculations. There are several reaction sites on a mineral surface, and, in the case of aluminosilicates, the dissolution chemistry is dictated by chemically distinct surface termination sites: Al and Si. Environmental factors such as pH determine the protonation state and configuration around these terminal sites. The dissolution mechanisms for Al- and Si-terminated sites in protonated, neutral, and deprotonated states are determined using density functional theory calculations. In all protonation states, Si are tetra-coordinated; however, the ability of Al to exist in tetra-, penta-, and hexa-coordination states makes the dissolution mechanisms for the two types of terminal sites fundamentally different. The calculated barrier heights for Al-terminated sites are predicted to be lower than those for Si-terminated sites, a trend that has been observed in experimental studies. The sensitivity of the calculations on the choice of density functionals and basis sets is tested using three functionals: B3LYP, PBE1PBE, and M05-2X, in combination with the 6-311+G(d,p) and MG3S basis sets. For all these calculations, the geometries of the stationary points along the reaction path and the barrier heights are presented.


Trails and physical activity: a review.
To provide a synthesis of research on trails and physical activity from the public health, leisure sciences, urban planning, and transportation literatures. A search of databases was conducted to identify studies published between 1980 and 2008. 52 studies were identified. The majority were cross-sectional (92%) and published after 1999 (77%). The evidence for the effects of trails on physical activity was mixed among 3 intervention and 5 correlational studies. Correlates of trail use were examined in 13 studies. Several demographic (eg, race, education, income) and environmental factors (eg, land-use mix and distance to trail) were related to trail use. Evidence from 31 descriptive studies identified several facilitators and barriers to trail use. Economic studies (n = 5) examining trails in terms of health or recreational outcomes found trails are cost-effective and produce significant economic benefits. There is a growing body of evidence demonstrating important factors that should be considered in promoting trail use, yet the evidence for positive effects of trails on physical activity is limited. Further research is needed to evaluate the effects of trails on physical activity. In addition, trail studies that include children and youth, older adults, and racial and ethnic minorities are a research priority.


The role of IGF-I in the development of cardiovascular disease in type 2 diabetes mellitus: is prevention possible?
The incidence of peripheral, cerebro- and cardiovascular disease (CVD) in patients with type 2 diabetes mellitus is approximately twice as high as in the non-diabetic population. Conventional cardiovascular risk factors such as plasma lipids, lipoproteins and hypertension only partially explain this excessive risk of developing atherosclerosis and CVD. Meta-analysis of studies performed in non-diabetic populations indicates that the risk of CVD increases continuously with glucose levels above 4.2 mmol/l. The glucose hypothesis suggests that treatment which normalizes glucose levels prevents or delays the long-term complications of diabetes mellitus. However, the outcome of the UK Prospective Diabetes Study demonstrates that glucose control does not completely prevent CVD.In healthy subjects, serum IGF-I levels peak in early adulthood, after which they gradually decrease with increasing age. Several observations suggest that there is a premature and progressive age-related decline in serum IGF-I bioactivity in type 2 diabetics, which eventually results in a (relative) IGF-I deficiency. In type 2 diabetics, close relationships have been demonstrated between glycaemic control and serum IGF-I levels, with worse control being associated with lower IGF-I levels. Several studies (in non-diabetics) suggest that lowered circulating IGF-I levels account for a poor outcome of CVD. We previously observed in a population-based study that a genetically determined lowered IGF-I expression increases the risk of myocardial infarction with type 2 diabetes. This genetic approach overcomes the problem that cross-sectional studies cannot distinguish whether changes in IGF-I levels are a cause or a consequence of a disease. IGF-I is an important metabolic regulatory hormone. In addition, IGF-I suppresses myocardial apoptosis and improves myocardial function in various models of experimental cardiomyopathy. Compared with other growth factors, the 'survival' effect of IGF-I on myocardium seems rather unique.Therefore, we hypothesize that the premature and progressive decline in serum IGF-I bioactivity in ageing patients with type 2 diabetics is an important pathophysiological abnormality. It contributes not only to elevated glucose and lipid levels, but also to the progression and the poor outcome of CVD. If this hypothesis is proven to be right, treatment with IGF-I as an adjunct to insulin offers great potential and might not only improve metabolic control but also reduce the incidence and prevalence of CVD in type 2 diabetes patients. However, there is as yet no experimental evidence that long-term (replacement) treatment with IGF-I prevents, delays or reduces CVD in type 2 diabetes patients. Clinical trials are necessary to prove that long-term IGF-I treatment, preferably in the form of a better-tolerated IGF-I/IGF-binding protein-3 complex, improves the overall cardiovascular risk in type 2 diabetes.


Hemispherical digital optical condensers with no lenses, mirrors, or moving parts.
We present a simple method for obtaining direct non-scanning images in the far-field with subwavelength resolution. Our approach relies on the use of a digital optical condenser comprised of an array of light emitting diodes uniformly distributed inside of a hollow hemisphere. We demonstrate experimental observation of minimum feature sizes of the order of λ/6 with the proposed technique. Although our experiments were performed at visible frequencies, we anticipate that the proposed approach to subwavelength resolution can be extended to the ultraviolet and infrared spectral regions.


High diversity, low disparity and small body size in plesiosaurs (Reptilia, Sauropterygia) from the Triassic-Jurassic boundary.
Invasion of the open ocean by tetrapods represents a major evolutionary transition that occurred independently in cetaceans, mosasauroids, chelonioids (sea turtles), ichthyosaurs and plesiosaurs. Plesiosaurian reptiles invaded pelagic ocean environments immediately following the Late Triassic extinctions. This diversification is recorded by three intensively-sampled European fossil faunas, spanning 20 million years (Ma). These provide an unparalleled opportunity to document changes in key macroevolutionary parameters associated with secondary adaptation to pelagic life in tetrapods. A comprehensive assessment focuses on the oldest fauna, from the Blue Lias Formation of Street, and nearby localities, in Somerset, UK (Earliest Jurassic: 200 Ma), identifying three new species representing two small-bodied rhomaleosaurids (Stratesaurus taylori gen et sp. nov.; Avalonnectes arturi gen. et sp. nov) and the most basal plesiosauroid, Eoplesiosaurus antiquior gen. et sp. nov. The initial radiation of plesiosaurs was characterised by high, but short-lived, diversity of an archaic clade, Rhomaleosauridae. Representatives of this initial radiation were replaced by derived, neoplesiosaurian plesiosaurs at small-medium body sizes during a more gradual accumulation of morphological disparity. This gradualistic modality suggests that adaptive radiations within tetrapod subclades are not always characterised by the initially high levels of disparity observed in the Paleozoic origins of major metazoan body plans, or in the origin of tetrapods. High rhomaleosaurid diversity immediately following the Triassic-Jurassic boundary supports the gradual model of Late Triassic extinctions, mostly predating the boundary itself. Increase in both maximum and minimum body length early in plesiosaurian history suggests a driven evolutionary trend. However, Maximum-likelihood models suggest only passive expansion into higher body size categories.


High power, single-frequency, monolithic fiber amplifier for the next generation of gravitational wave detectors.
Low noise, high power single-frequency lasers and amplifiers are key components of interferometric gravitational wave detectors. One way to increase the detector sensitivity is to increase the power injected into the interferometers. We developed a fiber amplifier engineering prototype with a pump power limited output power of 200 W at 1064 nm. No signs of stimulated Brillouin scattering are observed at 200 W. At the maximum output power the polarization extinction ratio is above 19 dB and the fractional power in the fundamental transverse mode (TEM 00) was measured to be 94.8 %. In addition, measurements of the frequency noise, relative power noise, and relative pointing noise were performed and demonstrate excellent low noise properties over the entire output power slope. In the context of single-frequency fiber amplifiers, the measured relative pointing noise below 100 Hz and the higher order mode content is, to the best of our knowledge, at 200 W the lowest ever measured. A long-term test of more than 695 h demonstrated stable operation without beam quality degradation. It is also the longest single-frequency fiber amplifier operation at 200 W ever reported.


Delayed hospital presentation in acute decompensated heart failure: clinical and patient reported factors.
Patients with acute decompensated heart failure (ADHF) often wait a considerable amount of time before going to the hospital. Prior studies have examined the reasons why such delays may occur, but additional studies are needed to identify modifiable factors contributing to these delays. To describe care-seeking delay times, factors associated with prolonged delay, and patient's thoughts and actions in adult men and women hospitalized with ADHF. We surveyed 1271 patients hospitalized with ADHF at 8 urban medical centers between 2007 and 2010. The average age of our study population was 73 years, 47% were female, and 72% had prior heart failure. The median duration of pre-hospital delay prior to hospital presentation was 5.3 h. Patients who delayed longer than the median were older, more likely to have diabetes, peripheral edema, to have symptoms that began in the afternoon, and to have contacted their medical provider(s) about their symptoms. Prolonged care seekers were less likely to have attributed their symptoms to ADHF, less likely to want to have bothered their doctor or family, and were more likely to be concerned about missing work due to their illness (all p values < 0.05). Care-seeking delays are common among patients with ADHF. A variety of factors contribute to these delays, which in some cases may represent efforts to manage ADHF symptoms at home. More research is needed to better understand the detrimental effects of these delays and how best to encourage timely care-seeking behavior in the setting of ADHF.


Multi-lingual search engine to access PubMed monolingual subsets: a feasibility study.
PubMed contains many articles in languages other than English but it is difficult to find them using the English version of the Medical Subject Headings (MeSH) Thesaurus. The aim of this work is to propose a tool allowing access to a PubMed subset in one language, and to evaluate its performance. Translations of MeSH were enriched and gathered in the information system. PubMed subsets in main European languages were also added in our database, using a dedicated parser. The CISMeF generic semantic search engine was evaluated on the response time for simple queries. MeSH descriptors are currently available in 11 languages in the information system. All the 654,000 PubMed citations in French were integrated into CISMeF database. None of the response times exceed the threshold defined for usability (2 seconds). It is now possible to freely access biomedical literature in French using a tool in French; health professionals and lay people with a low English language may find it useful. It will be expended to several European languages: German, Spanish, Norwegian and Portuguese.


Action of partially thiolated polynucleotides on the DNA polymerase alpha from regenerating rat liver.
The effects of partially thiolated polynucleotides on the DNA polymerase alpha from regenerating rat liver were investigated. The enzyme was isolated from the nuclear fraction essentially according to the method of Baril et al.; it was characterized as the alpha polymerase on the basis of its response to synthetic templates and its inhibition with N-ethylmaleimide. Although polycytidylic acid had no effect on the DNA polymerase alpha either as a template or as an inhibitor, partially thiolated polycytidylic acid (MPC) was found to be a potent inhibitor, its activity being directly related to its extent of thiolation (percentage of 5-mercaptocytidylate units in the polymer). In comparison, the DNA polymerase beta which was purified from normal rat liver nuclear fraction, was much less sensitive to inhibition by MPC. Analysis of the inhibition of the alpha polymerase by the method of Lineweaver and Burk showed that the inhibitory action of MPC was competitively reversible with the DNA template, but the binding of the 7.2%-thiolated MPC to the enzyme was much stronger than that of the template (Ki/Km less than 0.03). Polyuridylic acid as such showed some inhibitory activity which increased on partial thiolation, but the 8.4%-thiolated polyuridylic acid was less active than the 7.2% MPC. When MPC was annealed with polyinosinic acid, it lost 80% of its inhibitory activity in the double-stranded configuration. However, 1 to 2%-thiolated DNA isolates were significantly more potent inhibitors than were comparable (1.2%-thiolated) MPC and showed competitive reversibility with the unmodified (but "activated") DNA template. These results indicate that the inhibitory activities of partially thiolated polynucleotides depend not only on the percentage of 5-mercapto groups but also on the configuration, base composition, and other specific structural properties.


Synthesis and Biological Activity of a Cytostatic Inhibitor of MLLr Leukemia Targeting the DOT1L Protein.
Histone methyltransferase DOT1L catalyzes mono-, di- and trimethylation of histone 3 at lysine residue 79 (H3K79) and hypermethylation of H3K79 has been linked to the development of acute leukemias characterized by the MLL (mixed-lineage leukemia) rearrangements (MLLr cells). The inhibition of H3K79 methylation inhibits MLLr cells proliferation, and an inhibitor specific for DOT1L, pinometostat, was in clinical trials (Phase Ib/II). However, the compound showed poor pharmacological properties. Thus, there is a need to find new potent inhibitors of DOT1L for the treatment of rearranged leukemias. Here we present the design, synthesis, and biological evaluation of a small molecule that inhibits in the nM level the enzymatic activity of hDOT1L, H3K79 methylation in MLLr cells with comparable potency to pinometostat, associated with improved metabolic stability and a characteristic cytostatic effect.


Investigation of temporal vascular effects induced by focused ultrasound treatment with speckle-variance optical coherence tomography.
Focused ultrasound (FUS) can be used to locally and temporally enhance vascular permeability, improving the efficiency of drug delivery from the blood vessels into the surrounding tissue. However, it is difficult to evaluate in real time the effect induced by FUS and to noninvasively observe the permeability enhancement. In this study, speckle-variance optical coherence tomography (SVOCT) was implemented for the investigation of temporal effects on vessels induced by FUS treatment. With OCT scanning, the dynamic change in vessels during FUS exposure can be observed and studied. Moreover, the vascular effects induced by FUS treatment with and without the presence of microbubbles were investigated and quantitatively compared. Additionally, 2D and 3D speckle-variance images were used for quantitative observation of blood leakage from vessels due to the permeability enhancement caused by FUS, which could be an indicator that can be used to determine the influence of FUS power exposure. In conclusion, SVOCT can be a useful tool for monitoring FUS treatment in real time, facilitating the dynamic observation of temporal effects and helping to determine the optimal FUS power.


Kinetic properties and electron paramagnetic resonance spectra of the nitric oxide derivative of hemoglobin components of trout (Salmo irideus).
The binding of nitric oxide to hemoglobin components of trout (Salmo irideus), i.e., Hb trout I and Hb trout IV, has been studied by optical and electron paramagnetic resonance spectroscopy. Kinetic studies show that the Root effect in Hb trout IV is operative also for NO, since a large increase in the dissociation velocity constant (j(4)) is observed as the pH is decreased below 7. Moreover, the time course of the displacement of NO by CO is heterogeneous, suggesting that alpha and beta chains may have different j(4) values. Low-temperature X-band electron paramagnetic resonance spectra have been recorded with Hb trout I and IV saturated with NO at different pH values. The spectra of Hb trout IV are strongly pH-dependent. The high-pH form (pH 8.1) shows axial symmetry and no resolved hyperfine splitting, while the low-pH form is rhombic with a hyperfine splitting of 6.5 G in the g(z) region. The latter form reflects a more distorted site with a more significant delocalization of the unpaired electron on the proximal histidine; both features indicate a destabilization of the ligand binding at low pH. On the other hand, spectra of Hb trout I are axial at both pH values, with hyperfine splitting of 16.5 G, indicating that the site is not distorted and interacts with the ligand very strongly at either pH.


Progression of the morphogenetic furrow in the Drosophila eye: the roles of Hedgehog, Decapentaplegic and the Raf pathway.
During Drosophila eye development, Hedgehog (Hh) protein secreted by maturing photoreceptors directs a wave of differentiation that sweeps anteriorly across the retinal primordium. The crest of this wave is marked by the morphogenetic furrow, a visible indentation that demarcates the boundary between developing photoreceptors located posteriorly and undifferentiated cells located anteriorly. Here, we present evidence that Hh controls progression of the furrow by inducing the expression of two downstream signals. The first signal, Decapentaplegic (Dpp), acts at long range on undifferentiated cells anterior to the furrow, causing them to enter a 'pre-proneural' state marked by upregulated expression of the transcription factor Hairy. Acquisition of the pre-proneural state appears essential for all prospective retinal cells to enter the proneural pathway and differentiate as photoreceptors. The second signal, presently unknown, acts at short range and is transduced via activation of the Serine-Threonine kinase Raf. Activation of Raf is both necessary and sufficient to cause pre-proneural cells to become proneural, a transition marked by downregulation of Hairy and upregulation of the proneural activator, Atonal (Ato), which initiates differentiation of the R8 photoreceptor. The R8 photoreceptor then organizes the recruitment of the remaining photoreceptors (R1-R7) through additional rounds of Raf activation in neighboring pre-proneural cells. Finally, we show that Dpp signaling is not essential for establishing either the pre-proneural or proneural states, or for progression of the furrow. Instead, Dpp signaling appears to increase the rate of furrow progression by accelerating the transition to the pre-proneural state. In the abnormal situation in which Dpp signaling is blocked, Hh signaling can induce undifferentiated cells to become pre-proneural but does so less efficiently than Dpp, resulting in a retarded rate of furrow progression and the formation of a rudimentary eye.


Bayesian coalescent inference of past population dynamics from molecular sequences.
We introduce the Bayesian skyline plot, a new method for estimating past population dynamics through time from a sample of molecular sequences without dependence on a prespecified parametric model of demographic history. We describe a Markov chain Monte Carlo sampling procedure that efficiently samples a variant of the generalized skyline plot, given sequence data, and combines these plots to generate a posterior distribution of effective population size through time. We apply the Bayesian skyline plot to simulated data sets and show that it correctly reconstructs demographic history under canonical scenarios. Finally, we compare the Bayesian skyline plot model to previous coalescent approaches by analyzing two real data sets (hepatitis C virus in Egypt and mitochondrial DNA of Beringian bison) that have been previously investigated using alternative coalescent methods. In the bison analysis, we detect a severe but previously unrecognized bottleneck, estimated to have occurred 10,000 radiocarbon years ago, which coincides with both the earliest undisputed record of large numbers of humans in Alaska and the megafaunal extinctions in North America at the beginning of the Holocene.


Adaptive WTA with an analog VLSI neuromorphic learning chip.
In this paper, we demonstrate how a particular spike-based learning rule (where exact temporal relations between input and output spikes of a spiking model neuron determine the changes of the synaptic weights) can be tuned to express rate-based classical Hebbian learning behavior (where the average input and output spike rates are sufficient to describe the synaptic changes). This shift in behavior is controlled by the input statistic and by a single time constant. The learning rule has been implemented in a neuromorphic very large scale integration (VLSI) chip as part of a neurally inspired spike signal image processing system. The latter is the result of the European Union research project Convolution AER Vision Architecture for Real-Time (CAVIAR). Since it is implemented as a spike-based learning rule (which is most convenient in the overall spike-based system), even if it is tuned to show rate behavior, no explicit long-term average signals are computed on the chip. We show the rule's rate-based Hebbian learning ability in a classification task in both simulation and chip experiment, first with artificial stimuli and then with sensor input from the CAVIAR system.


Cortical and spinal mechanisms of task failure of sustained submaximal fatiguing contractions.
In this and the subsequent companion paper, results are presented that collectively seek to delineate the contribution that supraspinal circuits have in determining the time to task failure (TTF) of sustained submaximal contractions. The purpose of this study was to compare adjustments in supraspinal and spinal excitability taken concurrently throughout the performance of two different fatigue tasks with identical mechanical demands but different TTF (i.e., force-matching and position-matching tasks). On separate visits, ten healthy volunteers performed the force-matching or position-matching task at 15% of maximum strength with the elbow flexors to task failure. Single-pulse transcranial magnetic stimulation (TMS), paired-pulse TMS, paired cortico-cervicomedullary stimulation, and brachial plexus electrical stimulation were delivered in a 6-stimuli sequence at baseline and every 2-3 minutes throughout fatigue-task performance. Contrary to expectations, the force-matching task TTF was 42% shorter (17.5 ± 7.9 min) than the position-matching task (26.9 ± 15.11 min; p<0.01); however, both tasks caused the same amount of muscle fatigue (p = 0.59). There were no task-specific differences for the total amount or rate of change in the neurophysiologic outcome variables over time (p>0.05). Therefore, failure occurred after a similar mean decline in motorneuron excitability developed (p<0.02, ES = 0.35-0.52) coupled with a similar mean increase in measures of corticospinal excitability (p<0.03, ES = 0.30-0.41). Additionally, the amount of intracortical inhibition decreased (p<0.03, ES = 0.32) and the amount of intracortical facilitation (p>0.10) and an index of upstream excitation of the motor cortex remained constant (p>0.40). Together, these results suggest that as fatigue develops prior to task failure, the increase in corticospinal excitability observed in relationship to the decrease in spinal excitability results from a combination of decreasing intracortical inhibition with constant levels of intracortical facilitation and upstream excitability that together eventually fail to provide the input to the motor cortex necessary for descending drive to overcome the spinal cord resistance, thereby contributing to task failure.


Bistratified starburst amacrine cells in Sox2 conditional knockout mouse retina display ON and OFF responses.
Cell-intrinsic factors, in conjunction with environmental signals, guide migration, differentiation, and connectivity during early development of neuronal circuits. Within the retina, inhibitory starburst amacrine cells (SBACs) comprise ON types with somas in the ganglion cell layer (GCL) and dendrites stratifying narrowly in the inner half of the inner plexiform layer (IPL) and OFF types with somas in the inner nuclear layer (INL) and dendrites stratifying narrowly in the outer half of the IPL. The transcription factor Sox2 is crucial to this subtype specification. Without Sox2, many ON-type SBACs destined for the GCL settle in the INL while many that reach the GCL develop bistratified dendritic arbors. This study asked whether ON-type SBACs in Sox2-conditional knockout retinas exhibit selective connectivity only with ON-type bipolar cells or their bistratified morphology allows them to connect to both ON and OFF bipolar cells. Physiological data demonstrate that these cells receive ON and OFF excitatory inputs, indicating that the ectopically stratified dendrites make functional synapses with bipolar cells. The excitatory inputs were smaller and more transient in Sox2-conditional knockout compared with wild type; however, inhibitory inputs appeared largely unchanged. Thus dendritic stratification, rather than cellular identification, may be the major factor that determines ON vs. OFF connectivity. NEW & NOTEWORTHY Conditional knockout of the transcription factor Sox2 during early embryogenesis converts a monostratifying starburst amacrine cell into a bistratifying starburst cell. Here we show that these bistratifying starburst amacrine cells form functional synaptic connections with both ON and OFF bipolar cells. This suggests that normal ON vs. OFF starburst connectivity may not require distinct molecular specification. Proximity alone may be sufficient to allow formation of functional synapses.


Endovascular treatment of iliac artery rupture after septic embolization.
A 56-year man with multiple comorbidities and recent septic embolization presented claudication intermittens (Rutherford3) at right lower limb and complaint in right lower quadrant at abdominal palpation. Duplex and computed tomography angiogram (CTA) showed a 64mm-pseudo-aneurysm (PA) originating from right common iliac artery, occlusion of external iliac and patency of hypogastric artery. An urgent endovascular approach was preferred. By left brachial percutaneous access, coil embolization (Balt SPI™ and Cook MReye™) of hypogastric and common iliac artery and deployment of Amplatzer Vascular PlugII™ into the common iliac artery were performed. Completion angiography showed exclusion of PA. One-day, 3‑day and 1-month CTA proofed no vascularization of PA. No fever, no leukocytosis, no signs of infection occurred during follow-up and 10-month CTA showed the complete resolution of pseudoaneurysm.


Mycoplasma agalactiae MAG_5040 is a Mg2+-dependent, sugar-nonspecific SNase recognised by the host humoral response during natural infection.
In this study the enzymatic activity of Mycoplasma agalactiae MAG_5040, a magnesium-dependent nuclease homologue to the staphylococcal SNase was characterized and its antigenicity during natural infections was established. A UGA corrected version of MAG_5040, lacking the region encoding the signal peptide, was expressed in Escherichia coli as a GST fusion protein. Recombinant GST-MAG_5040 exhibits nuclease activity similar to typical sugar-nonspecific endo- and exonucleases, with DNA as the preferred substrate and optimal activity in the presence of 20 mM MgCl2 at temperatures ranging from 37 to 45°C. According to in silico analyses, the position of the gene encoding MAG_5040 is consistently located upstream an ABC transporter, in most sequenced mycoplasmas belonging to the Mycoplasma hominis group. In M. agalactiae, MAG_5040 is transcribed in a polycistronic RNA together with the ABC transporter components and with MAG_5030, which is predicted to be a sugar solute binding protein by 3D modeling and homology search. In a natural model of sheep and goats infection, anti-MAG_5040 antibodies were detected up to 9 months post infection. Taking into account its enzymatic activity, MAG_5040 could play a key role in Mycoplasma agalactiae survival into the host, contributing to host pathogenicity. The identification of MAG_5040 opens new perspectives for the development of suitable tools for the control of contagious agalactia in small ruminants.


Congenital hypothyroidism screening program in Turkey: a local evaluation.
It was aimed to evaluate the national congenital hypothyroidism program in terms of thyroid-stimulating hormone (TSH) cut-off level, frequency of cases that required treatment and the stages before treatment in the Kocaeli district area. This research was performed with the contribution of Kocaeli University Medical Faculty, Pediatric Endocrinology Department, and the Kocaeli Local Health District. 25,188 babies born in 2009 were evaluated. The previous laboratory data including heel prick samples and venous thyroid function tests (TSH, free/total T4 levels) of babies requiring investigation were evaluated retrospectively. 49,785 heel prick blood samples were collected from 25,188 babies born in our region. TSH levels of 3,355 babies in the first sampling were greater than the cut-off level (15 mIU/L) (recall rate was 13.3%). Venous sampling was required for 107 babies, and 39 of them needed to be treated (treatment rate was 1/645). Eleven of the babies who were treated were diagnosed with thyroid dysgenesis. Families of the babies who needed further venous sampling were given final results in an average of 28.5 days after the first heel sampling. We concluded that the recall rate is high, but raising the cut-off level for TSH may lead to overlooking the diagnosis of thyroid dysgenesis. The duration for providing final results to the families is quite long. It is necessary to take venous blood samples in the pediatric endocrinology units to reduce this duration.


Morphometry of organization of middle meningeal artery through the analysis of bony canal in human's skull: A clinico-anatomical and embryological insight.
Middle meningeal artery (MMA) is the largest branch of the maxillary artery supplying meninges of the cranial cavity. The complexity of MMA development gives many opportunities for anatomical variation. Besides, the variant MMA can be easily injured when dealing with fractures of the base of the skull, epidural hematomas, and bypass procedures. Although various aberrant origins of the MMA have been documented in the literature, there is a lack of detailed morphometric aspects of this important arterial segment. Thus, in this study, we investigated the anatomical organization of the MMA through the bony canal measurements from human skulls to improve surgical results. Seventy-five adult dry skulls were investigated. Angle of the main trunk, length of the main trunk, angle between the frontal and parietal branches, length of the frontal branch, length of the parietal branch, and length of the bony tunnel formed by the frontal branch were measured bilaterally. In the present study, we found significant differences between the parameters such as length of frontal (P = 0.034) and parietal (P = 0.023) branches and length of bony tunnel (P = 0.045) of right and left sides, but there was no significant difference found in the rest of the parameters. Morphometry of the bony canal of MMA shall be important for safely expose and preserve the artery during craniotomy with careful drilling and shall be useful for those who have interest in this anatomical site.


Assessment of cardiovascular parameters during dental procedures under the effect of benzodiazepines: a double blind study.
The purpose of this study was to evaluate cardiovascular parameters during dental procedures: systolic, diastolic, and mean blood pressures, and heart rate. Nineteen healthy normotensive patients (18-56 years of age) received restorative treatment on three maxillary molars. The patients were continuously monitored by a non-invasive automatic monitor for blood pressure and heart rate during the pre-, trans-, and post-operative periods at the following stages: 15 min prior to anesthesia; during topical anesthesia; during infiltrative anesthesia; for 5 minutes immediately after; during cavity preparation; during restorative procedure; for 10 min after completion. Patients were divided into three groups: A (without pre-medication), B (preceded by 10 mg diazepam), and C (preceded by placebo). All patients received infiltrative anesthesia containing 1.8 mL of 2% lidocaine (36 mg) with epinephrine 1:100,000 (18 microg). There were no changes in the parameters during the clinical procedures. When groups were compared, there were significant differences in diastolic arterial pressures during anesthesia.


Trachoma Prevalence After Discontinuation of Mass Azithromycin Distribution.
As the World Health Organization seeks to eliminate trachoma by 2020, countries are beginning to control the transmission of trachomatous inflammation-follicular (TF) and discontinue mass drug administration (MDA) with oral azithromycin. We evaluated the effect of MDA discontinuation on TF1-9 prevalence at the district level. We extracted from the available data districts with an impact survey at the end of their program cycle that initiated discontinuation of MDA (TF1-9 prevalence <5%), followed by a surveillance survey conducted to determine whether TF1-9 prevalence remained below the 5% threshold, warranting discontinuation of MDA. Two independent analyses were performed, 1 regression based and 1 simulation based, that assessed the change in TF1-9 from the impact survey to the surveillance survey. Of the 220 districts included, TF1-9 prevalence increased to >5% from impact to surveillance survey in 9% of districts. Regression analysis indicated that impact survey TF1-9 prevalence was a significant predictor of surveillance survey TF1-9 prevalence. The proportion of simulations with >5% TF1-9 prevalence in the surveillance survey was 2%, assuming the survey was conducted 4 years after MDA. An increase in TF1-9 prevalence may represent disease resurgence but could also be due to measurement error. Improved diagnostic tests are crucial to elimination of TF1-9 as a public health problem.


Superior ion release properties and antibacterial efficacy of nanostructured zeolites ion-exchanged with zinc, copper, and iron.
Antimicrobial zeolites ion-exchanged with inexpensive transition metal ions (such as zinc, copper, and iron) are critically important for a broader adoption of the materials for public health applications. Due to the high surface area and small particle sizes, nanozeolites are particularly promising in enhancing the efficacy of the zeolite-based antimicrobial materials. By using highly-crystalline nanostructured zeolites (FAU) with textural mesoporosity, we report a comprehensive study on the materials characteristics of zinc-, copper-, and iron-ion exchanged nanozeolites, the ion release properties, and antibacterial efficacy against methicillin-resistant Staphylococcus aureus (MRSA), as well as a comparison of the properties to those obtained for the corresponding microsized zeolites. Superior ion release properties were observed for both zinc and copper ion-exchanged nanostructured zeolite X, with ion release up to 73% for zinc and 36% for copper of their initial loadings, as compared to 50% and 12%, respectively, for the corresponding microsized zeolites, validating the importance of nanostructuring for enhanced ion diffusion through zeolite pore channels. The 2 hours minimum bactericidal concentration (MBC) in saline for the copper ion-exchanged nanostructured zeolite X was 32 μg mL-1, half the corresponding microsized zeolite X MBC of 64 μg mL-1. Our results established nanostructured zeolite X as a superior host material for metal ion-based antimicrobials, with the aforementioned improvements for copper-exchanged nanozeolites compared to previous studies.


A new genus, Helgoeca gen. nov., for a nudiform choanoflagellate.
A new genus, Helgoeca gen. nov., has been designated to accommodate a nudiform loricate choanoflagellate (American Type Culture Collection strain ATCC 50073) that was incorrectly attributed to the tectiform genus Acanthoecopsis (=Acanthocorbis). The first indication that this species might be nudiform came from a four-gene phylogeny of the choanoflagellates which recovered ATCC 50073 within a strongly supported monophyletic clade comprising two other nudiform taxa. Fortunately an isolate of the species in question was available from the ATCC and when observed in rapidly growing culture it was immediately apparent that this species divided with the production of 'naked' motile cells; a typically nudiform character. The beaker-shaped lorica of this species consists of an outer layer of approximately 11 longitudinal costae, which terminate anteriorly as spines, and an equal or larger number of helical costae, with a left-handed conformation, each of which terminates anteriorly adjacent to the base of a spine. The pattern of costae in this species is indistinguishable from that of Acanthocorbis nana Thomsen and for this reason A. nana has been transferred to the new genus Helgoeca gen. nov., as the type species.


Whole Exome Sequencing Identifies an Adult-Onset Case of Methylmalonic Aciduria and Homocystinuria Type C (cblC) with Non-Syndromic Bull's Eye Maculopathy.
Methylmalonic aciduria and homocystinuria type C (cblC), a disorder of vitamin B12 (cobalamin) metabolism caused by mutations in the MMACHC gene, presents with many systemic symptoms, including neurological, cognitive, psychiatric, and thromboembolic events. Retinal phenotypes, including maculopathy, pigmentary retinopathy, and optic atrophy are common in early onset form of the disease but are rare in adult onset forms. An adult Hispanic female presented with decreased central vision, bilateral pericentral ring scotomas and bull's eye-appearing macular lesions at 28 years of age. Her medical history was otherwise unremarkable except for iron deficiency anemia and both urinary tract and kidney infections. Screening of the ABCA4 gene, mutations in which frequently cause bull's eye maculopathy, was negative. Subsequently, analysis with whole exome sequencing was performed. Whole exome sequencing discovered compound heterozygous mutations in MMACHC, c.G482A:p.Arg161Gln and c.270_271insA:p.Arg91Lysfs*14, which segregated with the disease in the family. The genetic diagnosis was confirmed by biochemical laboratory testing, showing highly elevated urine methylmalonic acid/creatinine and homocysteine levels, and suggesting disease management with hydroxycobalamin injections and carnitine supplementation. In summary, a unique case of an adult patient with bull's eye macular lesions and no clinically relevant systemic symptoms was diagnosed with cblC by genetic screening and follow-up biochemical laboratory tests.


Structure and thermodynamics of a mixture of patchy and spherical colloids: A multi-body association theory with complete reference fluid information.
A mixture of solvent particles with short-range, directional interactions and solute particles with short-range, isotropic interactions that can bond multiple times is of fundamental interest in understanding liquids and colloidal mixtures. Because of multi-body correlations, predicting the structure and thermodynamics of such systems remains a challenge. Earlier Marshall and Chapman [J. Chem. Phys. 139, 104904 (2013)] developed a theory wherein association effects due to interactions multiply the partition function for clustering of particles in a reference hard-sphere system. The multi-body effects are incorporated in the clustering process, which in their work was obtained in the absence of the bulk medium. The bulk solvent effects were then modeled approximately within a second order perturbation approach. However, their approach is inadequate at high densities and for large association strengths. Based on the idea that the clustering of solvent in a defined coordination volume around the solute is related to occupancy statistics in that defined coordination volume, we develop an approach to incorporate the complete information about hard-sphere clustering in a bulk solvent at the density of interest. The occupancy probabilities are obtained from enhanced sampling simulations but we also develop a concise parametric form to model these probabilities using the quasichemical theory of solutions. We show that incorporating the complete reference information results in an approach that can predict the bonding state and thermodynamics of the colloidal solute for a wide range of system conditions.


Fault Tolerant Sliding Mode Predictive Control for Uncertain Steer-by-Wire System.
The Steer-by-Wire (SbW) system is an electronically controlled steering system that is able to improve steering capability without mechanical links between the steering wheel and the front wheels. However, failure of the SbW system actuator may lead to steering performance degradation and result in instability. In this paper, a fault tolerant sliding mode predictive control (SMPC) strategy for an SbW system is proposed. The sliding mode control is applied to improve the robustness of the model predictive control (MPC) in the presence of modeling uncertainties and disturbances, while the MPC is applied to enhance the fault tolerant capability of the steering control processes. The chaos particle swarm optimization (CPSO) algorithm is introduced to optimize the MPC and a two-stage Kalman filter is introduced to simultaneously provide fault information and state estimation. The performance of the proposed approach is validated through computer simulation. The results demonstrate that the proposed SMPC-CPSO controller is more robust and provides better tracking performance in the presence of model uncertainties, disturbance, and actuator faults than SCMP-PSOs (heterogeneous comprehensive learning particle swarm optimization, evolutionary particle swarm optimizer, etc), SMPC-differential evolution, MPC, SMPC, and MPC-PSO.