Sample size requirement to detect an intervention effect at the end of follow-up in a longitudinal cluster randomized trial.
It is often anticipated in a longitudinal cluster randomized clinical trial (cluster-RCT) that the course of outcome over time will diverge between intervention arms. In these situations, testing the significance of a local intervention effect at the end of the trial may be more clinically relevant than evaluating overall mean differences between treatment groups. In this paper, we present a closed-form power function for detecting this local intervention effect based on maximum likelihood estimates from a mixed-effects linear regression model for three-level continuous data. Sample size requirements for the number of units at each data level are derived from the power function. The power function and the corresponding sample size requirements are verified by a simulation study. Importantly, it is shown that sample size requirements computed with the proposed power function are smaller than that required when testing group mean difference using data only at the end of trial and ignoring the course of outcome over the entire study period.


Fixing health care from the inside, today.
Today, you are about as safe in a U.S. hospital as you would be parachuting off a bridge or a building. But it doesn't have to be that way. Right now, some hospitals are making enormous short-term improvements, with no legislation or market reconfiguration and little or no capital investment. Instead of waiting for sweeping changes in market mechanisms, these institutions are taking an operations approach to patient care. In case after detailed case, the article describes how doctors, nurses, technicians, and managers are radically increasing the effectiveness of patient care and dramatically lowering its cost by applying the same capabilities in operations design and improvement that drive the famous Toyota Production System. They are removing ambiguity in the output, responsibilities, connections, and methods of their work processes. These changes-which can be done in the course of an ordinary workday, sometimes in a matter of hours-are designed to make the following crystal clear: Which patient gets which procedure (output); Who does which aspect of the job (responsibility); Exactly which signals are used to indicate that the work should begin (connection); and Precisely how each step is carried out (method). Equally important, managers are being transformed from rescuers who arrive with ready-made solutions into problem solvers who help colleagues learn the experimental method. Thus, these hospitals are breaking free of the work-around culture that routinely obscures the root causes of so many problems, creates so much waste, and leads to so many unnecessary deaths.


Displacement and strain calculations by the phase shift method.
The phase shift method, well known in holographic interferometry, is applied to the deformation of line gratings. The method uses the moire effect but it determines local displacement or strain from the grey values of three shifted images instead of the coordinates of the fringes. The basic equations are derived from the transmittance function. The theoretical error with respect to a given displacement field is calculated by simulation. Real errors are investigated by related plotter-generated line gratings. The phase shift method is especially suitable for automatic digital image processing.


Mortality from causes amenable and non-amenable to medical care: the experience of eastern Europe.
To investigate comparative national trends in mortality from conditions amenable to timely, appropriate medical care and from those considered not to be amenable to such care. Analysis of trends in direct age standardised mortality from the 1950s to 1987. Four eastern European nations (Hungary, Czechoslovakia, Poland, the German Democratic Republic) and two western European (the Federal Republic of Germany and England and Wales) and two North American nations (United States and Canada). The total populations of the relevant countries during the period examined. Proportional changes over time in age standardised mortality. Mortality from amenable and non-amenable causes was restricted to the age group 0-64. A divergence in the trends for all cause mortality between eastern Europe and the western nations occurred in about 1970, when the rates in western countries steadily declined but those in eastern Europe remained fairly static. In the age group 0-64 mortality from causes considered amenable to medical care fell less quickly in eastern Europe than in the West, particularly after 1970. In the same age group, mortality from non-amenable causes rose in eastern European countries from the late 1960s compared with substantial declines in such mortality in the West. Non-amenable causes of death seem to be the principal, but not exclusive, reason for lack of improvement in trends in all cause mortality in eastern Europe from 1970. The agenda for action in eastern Europe should give priority to a healthier lifestyle and improvement of the environment though not neglect enhancements in the quality and efficiency of direct health services.


Climate effects of emission standards: the case for gasoline and diesel cars.
Passenger transport affects climate through various mechanisms involving both long-lived and short-lived climate forcers. Because diesel cars generally emit less CO(2) than gasoline cars, CO(2) emission taxes for vehicle registrations and fuels enhance the consumer preference for diesel cars over gasoline cars. However, with the non-CO(2) components, which have been changed and will be changed under the previous and upcoming vehicle emission standards, what does the shift from gasoline to diesel cars mean for the climate mitigation? By using a simple climate model, we demonstrate that, under the earlier emissions standards (EURO 3 and 4), a diesel car causes a larger warming up to a decade after the emissions than a similar gasoline car due to the higher emissions of black carbon and NO(X) (enhancing the O(3) production). Beyond a decade, the warming caused by a diesel car becomes, however, weaker because of the lower CO(2) emissions. As the latter emissions standards (EURO 5 and 6) are phased in, the short-term warming due to a diesel car becomes smaller primarily due to the lower black carbon emissions. Thus, although results are subject to restrictive assumptions and uncertainties, the switch from gasoline to diesel cars encouraged by CO(2) taxes does not contradict with the climate mitigation focusing on long-term consequences.


Tracking Inhibitory Control in Youth With ADHD: A Multi-Modal Neuroimaging Approach.
A decreased ability to inhibit a speeded motor response is a well-studied deficit in Attention Deficit Hyperactivity Disorder (ADHD), and has been proposed as an endophenotype. Inhibitory control has been assessed reliably with the Stop Signal Task (SST) and is associated with prior documented differences in regional brain function using f-MRI. Here, we advance on these findings by examining their structural connectivity and white matter integrity with the goal of identifying a network underlying a core cognitive deficit in ADHD. Healthy controls (N=16) and youth diagnosed with ADHD (N=60) were recruited through the Province of Ontario Neurodevelopmental Disorders Network (POND) and the Hospital for Sick Children. An f-MRI activation difference map was co-registered with each participant's white matter imaging data, representing the specific network nodes where ADHD youth diverged significantly from controls while performing the SST. Probabilistic tractography was applied from these nodes, and white matter integrity indices such as fractional anisotropy (FA) within the tracts of interest were contrasted between the groups and correlated with SST output measures, including the measure of inhibitory control, the stop signal reaction time (SSRT). The tracts that connected the network nodes belonged primarily to the inferior fronto-occipital fasciculus (IFOF) and cingulum. ADHD subjects showed trend differences in FA compared to controls between right inferior frontal gyrus (IFG) and right superior temporal gyrus (P= 0.09), right IFG and right posterior cingulate (P= 0.01), right anterior cingulate to posterior cingulate (p= 0.08), and between left middle temporal gyrus (BA 39) and left posterior cingulate (P=0.02). A trend correlation was found between radial diffusivity within IFG to STG white matter (IFOF) and SSRT. We identified potential white matter tracts related to deficient inhibitory control, elucidating the brain mechanisms of an important cognitive deficit in ADHD. These findings could be integrated into future endophenotypic biomarker studies, incorporating altogether brain structure, function, and behavior for future studies of ADHD and other psychiatric conditions that exhibit this deficit.


Three-dimensional preparation and imaging reveal intrinsic microtubule properties.
We present an experimental investigation of microtubule dynamic instability in three dimensions, based on laser light-sheet fluorescence microscopy. We introduce three-dimensional (3D) preparation of Xenopus laevis egg extracts in Teflon-based cylinders and provide algorithms for 3D image processing. Our approach gives experimental access to the intrinsic dynamic properties of microtubules and to microtubule population statistics in single asters. We obtain evidence for a stochastic nature of microtubule pausing.


Bordetella petrii sp. nov., isolated from an anaerobic bioreactor, and emended description of the genus Bordetella.
A novel Bordetella species was isolated from an anaerobic, dechlorinating bioreactor culture enriched from river sediment. The only strain, Se-1111R(T) (= DSM 12804T = CCUG 43448T), for which the name Bordetella petrii is proposed, is designated the type strain of the novel species. Strain Se-1111R(T) was isolated from the dechlorinating mixed culture due to its ability to anaerobically reduce selenate to elemental selenium. Comparative 16S rDNA sequence analysis showed a close relationship between Se-1111R(T) and members of the genus Bordetella within the beta-Proteobacteria. This close phylogenetic relatedness was also reflected in several metabolic properties of Se-1111R(T), including its incapacity to utilize carbohydrates, by the high G+C content (63.8 mol%) of its DNA and by the presence of Q-8 as the major isoprenoid quinone. DNA-DNA hybridization experiments with type strains of all species of the genus Bordetella and closely related species Achromobacter xylosoxidans subsp. denitrificans provided further evidence for the assignment of strain Se-1111R(T) as a novel species of the genus Bordetella. This genus currently consists of seven aerobic species, all of which are known to occur in close pathogenic, opportunistic or possibly commensal relationships with various host organisms. B. petrii is the first member of this genus isolated from the environment and capable of anaerobic growth. The proposal of the novel species and an emended description of the genus Bordetella is presented.


Thyroid dysfunction after radiotherapy in children with Hodgkin's disease.
Thyroid function was measured in 119 children, 16 years of age or less, after radiotherapy (XRT) for Hodgkin's disease. Thyroid abnormalities developed in 4 of 24 children (17%) who received 2600 rad or less, and in 74 of 95 children (78%) who received greater than 2600 rad to the cervical area, including the thyroid. The abnormality in all but three (one with hyperthyroidism and two with thyroid nodules) included the development of elevated levels of thyroid stimulating hormone (TSH). Age, sex, and administration of chemotherapy were not significant factors in the development of thyroid dysfunction. All children had lymphangiograms (LAG) and no time relationship was noted between thyroid dysfunction and LAG-XRT interval. The mean interval from radiotherapy to documented thyroid dysfunction was 18 months in the low-dose group and 31 months in the high-dose group, with most patients becoming abnormal within 3 to 5 years. Of interest was a spontaneous return of TSH to within normal limits in 20 children and substantial improvement in another 7. This study confirms the occurrence of dose-related occult hypothyroidism in children following external irradiation of the neck.


Effects of glutamine supplementation on oxidative stress-related gene expression and antioxidant properties in rats with streptozotocin-induced type 2 diabetes.
There are close links among hyperglycaemia, oxidative stress and diabetic complications. Glutamine (GLN) is an amino acid with immunomodulatory properties. The present study investigated the effect of dietary GLN on oxidative stress-relative gene expressions and tissue oxidative damage in diabetes. There were one normal control (NC) and two diabetic groups in the present study. Diabetes was induced by an intraperitoneal injection of nicotinamide followed by streptozotocin (STZ). Rats in the NC group were fed a regular chow diet. In the two diabetic groups, one group (diabetes mellitus, DM) was fed a common semi-purified diet while the other group received a diet in which part of the casein was replaced by GLN (DM-GLN). GLN provided 25% of total amino acid N. The experimental groups were fed the respective diets for 8 weeks, and then the rats were killed for further analysis. The results showed that blood thioredoxin-interacting protein (Txnip) mRNA expression in the diabetic groups was higher than that in the NC group. Compared with the DM group, the DM-GLN group had lower glutamine fructose-6-phosphate transaminase 1, a receptor of advanced glycation end products, and Txnip gene expressions in blood mononuclear cells. The total antioxidant capacity was lower and antioxidant enzyme activities were altered by the diabetic condition. GLN supplementation increased antioxidant capacity and normalised antioxidant enzyme activities. Also, the renal nitrotyrosine level and Txnip mRNA expression were lower when GLN was administered. These results suggest that dietary GLN supplementation decreases oxidative stress-related gene expression, increases the antioxidant potential and may consequently attenuate renal oxidative damage in rats with STZ-induced diabetes.


Order-disorder phase transition in an anhydrous pyrazole-based proton conductor: the enhancement of electrical transport properties.
The crystal structure of 1H-pyrazol-2-ium hydrogen oxalate has been studied at 100 K. It consists of two-dimensional layers built with one-dimensional chains that contain pyrazolium and oxalate acids bonded by N-HO and O-HO hydrogen bonds. According to the X-ray data and the Quantum Theory of Atoms in Molecules, it was shown that weak and moderate hydrogen bonds are present in the crystal at room temperature. The thermal stability was studied with the DSC, TGA, and DTG methods: three endothermic peaks are observed at 384, 420, and 469 K. Conductivity measurements have been performed in the temperature range from 300 to 433 K. At 383 K the pyrazole-oxalic acid framework loses its rigidity and the crystal undergoes an ordered-disordered phase transition. At this temperature, the value of the activation energy of proton conductivity changes from 1.14 to 2.31 eV. The proton conduction pathways and the transport mechanism have been studied with theoretical methods.


Consequences of seeded cell type on vascularization of tissue engineering constructs in vivo.
Implantation of tissue engineering constructs is a promising technique to reconstruct injured tissue. However, after implantation the nutrition of the constructs is predominantly restricted to vascularization. Since cells possess distinct angiogenic potency, we herein assessed whether scaffold vitalization with different cell types improves scaffold vascularization. 32 male balb/c mice received a dorsal skinfold chamber. Angiogenesis, microhemodynamics, leukocyte-endothelial cell interaction and microvascular permeability induced in the host tissue after implantation of either collagen coated poly (L-lactide-co-glycolide) (PLGA) scaffolds (group 4), additionally seeded with osteoblast-like cells (OLCs, group 1), bone marrow mesenchymal stem cells (bmMSCs, group 2) or a combination of OLCs and bmMSCs (group 3) were analyzed repetitively over 14 days using intravital fluorescence microscopy. Apart from a weak inflammatory response in all groups, vascularization was found distinctly accelerated in vitalized scaffolds, indicated by a significantly increased microvascular density (day 6, group 1: 202+/-15 cm/cm(2), group 2: 202+/-12 cm/cm(2), group 3: 194+/-8 cm/cm(2)), when compared with controls (group 4: 72+/-5 cm/cm(2)). This acceleration was independent from the seeded cell type. Immunohistochemistry revealed in vivo VEGF expression in close vicinity to the seeded OLCs and bmMSCs. Therefore, the observed lack of cell type confined differences in the vascularization process suggests that the accelerated vascularization of vitalized scaffolds is VEGF-related rather than dependent on the potential of bmMSCs to differentiate into specific vascular cells.


Sympathetic neural reactivity to mental stress in offspring of hypertensive parents: 20 years revisited.
A number of recent studies have highlighted large interindividual variability of muscle sympathetic nerve activity (MSNA) responsiveness to mental stress in humans. The purpose of this study was to examine blood pressure (BP) and MSNA responsiveness to mental stress in a large and generalizable cohort of young adults with and without family history of hypertension (FHH). We hypothesized that subjects with FHH would demonstrate greater sympathoexcitation to mental stress than subjects without FHH. A total of 87 subjects (55 men and 32 women, 18-40 yr of age) from recently published (n = 45) and ongoing (n = 42) studies were examined; 57 subjects (19 with FHH and 38 without FHH) had complete MSNA recordings at baseline. Heart rate (HR), BP, and MSNA were recorded during 5 min of supine rest and 5 min of mental stress (mental arithmetic). Resting MSNA and HR were not statistically different between subjects with and without FHH (P > 0.05), whereas resting mean arterial pressure was higher in subjects with FHH (86 ± 2 vs. 80 ± 1 mmHg, P < 0.05). Mental stress increased MSNA in subjects with FHH (Δ5 ± 1 bursts/min), but not in subjects without FHH [Δ1 ± 1 burst/min, P < 0.01 (time × group)]. Mental stress increased mean arterial pressure (Δ12 ± 1 and Δ10 ± 1 mmHg, P < 0.001) and HR (Δ19 ± 2 and Δ16 ± 2 beats/min, P < 0.001) in subjects with and without FHH, but these increases were not different between groups [P ≥ 0.05 (time × group)]. MSNA and BP reactivity to mental stress were not correlated in either group. In conclusion, FHH was associated with heightened MSNA reactivity to mental stress, despite a dissociation between MSNA and BP responsiveness.


An SREBP-responsive microRNA operon contributes to a regulatory loop for intracellular lipid homeostasis.
Sterol regulatory element-binding proteins (SREBPs) have evolved as a focal point for linking lipid synthesis with other pathways that regulate cell growth and survival. Here, we have uncovered a polycistrionic microRNA (miRNA) locus that is activated directly by SREBP-2. Two of the encoded miRNAs, miR-182 and miR-96, negatively regulate the expression of Fbxw7 and Insig-2, respectively, and both are known to negatively affect nuclear SREBP accumulation. Direct manipulation of this miRNA pathway alters nuclear SREBP levels and endogenous lipid synthesis. Thus, we have uncovered a mechanism for the regulation of intracellular lipid metabolism mediated by the concerted action of a pair of miRNAs that are expressed from the same SREBP-2-regulated miRNA locus, and each targets a different protein of the multistep pathway that regulates SREBP function. These studies reveal an miRNA "operon" analogous to the classic model for genetic control in bacterial regulatory systems.


Survey of Meloidogyne incognita and Thielaviopsis basicola: Their Impact on Cotton Fruiting and Producers' Management Choices in Infested Fields.
A survey of 100 cotton fields selected randomly in 1995 and 1996 was conducted in the High Plains of Texas to determine the incidence and potential severity of Meloidogyne incognita and Thielaviopsis basicola. Information was obtained from producers for each field on their nematicide application rates and fungicide seed treatments. The percent of squares and bolls set was evaluated for 20 plants in each field during late July 1995 and early August 1996. Thielaviopsis basicola was identified in 55% of the fields in 1995 and 73% of the irrigated fields in 1996. Meloidogyne incognita was found in 39% and 43% of the fields in 1995 and 1996, respectively. Both M. incognita and T. basicola were found together in approximately 30% of the fields. The average rate of aldicarb used in 1995 and 1996 was higher when fields were infested with both T. basicola and M. incognita than for fields infested with none or only one of the pathogens. However, there was no relationship between the use of fungicide treatments active against T. basicola and the potential for root necrosis, or presence of either or both pathogens (T. basicola and M. incognita). Aldicarb rates and usage of fungicide seed treatments were chosen by producers before fields were surveyed (i.e., the survey did not influence grower practices). In 1995, but not in 1996, the association of M. incognita and potential root necrosis (based on a bioassay from soil samples) was negatively correlated with the number of squares, percentage of squares set, and percentage of bolls set. The association between M. incognita and T. basicola, or potential severity of root necrosis, could not be correlated with fruit attributes in 1996 under warm spring conditions but was negatively correlated with fruit attributes in 1995 under cool spring conditions.


What constitutes 'good practice' in early intervention for psychosis? Analysis of clinical guidelines.
Early Intervention in Psychosis (EIP) services have been implemented with the dual aims of preventing harmful outcomes associated with early-onset psychosis and improving prognosis. However, concerns have been raised regarding the ethical implications of involving young people in EIP services. One way to ensure high ethical standards and promote good practice in EIP delivery is through governance of clinical practice. This study aimed to investigate the normative dimensions of good practice in EIP through examination of clinical guideline documents published in England over the past 15 years. A total of 14 clinical guidelines and relevant policy documents for EIP were retrieved and analysed using a mixed inductive and deductive thematic approach. Themes were derived from the data itself, whereas the development of broader categories was performed through a constant comparison with the scientific literature describing ethical issues in EIP. Ethical touchpoints of good practice in EIP included both procedural and substantive factors, which were seen to be interdependent and mutually constitutive. These ethical touchpoints were largely implicit in the documents analysed. Procedural requirements of EIP service delivery consisted of norms and rules pertaining to EIP service structure, adherence to codes of ethics, inclusivity, patient and family centredness and appropriate treatment provision. Substantive factors consisted of moral attributes that should be cultivated by healthcare professionals working in EIP: competency, empathy, sensitivity and trustworthiness. We argue that, to ensure good practice in EIP, procedural and substantive ethical expectations embedded in EIP guideline documents should be made explicit in EIP service and care delivery. We suggest that the procedural and substantive factors highlighted in this paper contribute useful dimensions for the eventual evaluation of good practice in EIP services across England.


Effects of de- and remineralization of dentin on bond strengths yielded by one-, three-, and four-step adhesives.
To assess the effect of different peri- and intertubular dentin mineralization conditions and etching on shear bond strength in vitro. One hundred fifty crowns of extracted bovine incisors were embedded in resin and ground to expose the buccal coronal dentin. Sixty specimens were subjected to a demineralizing solution (DS) and another 60 teeth to a bacterial-based laboratory caries model (S. mutans, SM). Thirty specimens of each demineralization protocol (DS and SM) were randomly selected and remineralized (-R). Thirty sound dentin specimens served as control (C). Resin composite buildups (Tetric) were bonded after application of one of the following adhesives: a one-step self-etching adhesive (Xeno III), and a self-etching adhesive (Syntac Classic) without (three-step) and with prior additional 35% phosphoric acid etching (etch-and-rinse, four-step). Teeth were subjected to shear bond strength testing in a universal testing device at a crosshead speed of 0.5 mm/min (Ultradent method). Bond strength value for group C ranged from 6.3 to 8.4 MPa (p > 0.05). DS and DS-R samples showed in creased bond strength with the one-step adhesive (11.6 MPa, p < 0.05), whereas the three-step adhesive with additional etching showed decreased bond strength (3.2 MPa, p < 0.05). SM samples showed the lowest bond strength of all adhesive systems (range 1.1 to 1.5 MPa, p > 0.05). Remineralization showed no effect on the latter group. The degree of mineralization of the dentin is important for adhesion. Additional etching with phosphori acid reduced bond strength of a three-step adhesive.


EPA-ng: Massively Parallel Evolutionary Placement of Genetic Sequences.
Next generation sequencing (NGS) technologies have led to a ubiquity of molecular sequence data. This data avalanche is particularly challenging in metagenetics, which focuses on taxonomic identification of sequences obtained from diverse microbial environments. Phylogenetic placement methods determine how these sequences fit into an evolutionary context. Previous implementations of phylogenetic placement algorithms, such as the evolutionary placement algorithm (EPA) included in RAxML, or PPLACER, are being increasingly used for this purpose. However, due to the steady progress in NGS technologies, the current implementations face substantial scalability limitations. Herein, we present EPA-NG, a complete reimplementation of the EPA that is substantially faster, offers a distributed memory parallelization, and integrates concepts from both, RAxML-EPA and PPLACER. EPA-NG can be executed on standard shared memory, as well as on distributed memory systems (e.g., computing clusters). To demonstrate the scalability of EPA-NG, we placed $1$ billion metagenetic reads from the Tara Oceans Project onto a reference tree with 3748 taxa in just under $7$ h, using 2048 cores. Our performance assessment shows that EPA-NG outperforms RAxML-EPA and PPLACER by up to a factor of $30$ in sequential execution mode, while attaining comparable parallel efficiency on shared memory systems. We further show that the distributed memory parallelization of EPA-NG scales well up to 2048 cores. EPA-NG is available under the AGPLv3 license: https://github.com/Pbdas/epa-ng.


Life Course Trajectories of Cardiovascular Risk Factors in Women With and Without Hypertensive Disorders in First Pregnancy: The HUNT Study in Norway.
Background Women with hypertensive pregnancy disorders have adverse levels of cardiovascular risk factors. It is unclear how this adverse risk factor profile evolves during adult life. We compared life course trajectories of cardiovascular risk factors in women with preeclampsia or gestational hypertension in their first pregnancy to normotensive women. Methods and Results We linked information on cardiovascular risk factors from the population-based HUNT (Nord-Trøndelag Health Study) surveys with pregnancy information from the Medical Birth Registry of Norway. Trajectories of cardiovascular risk factors were constructed for 22 308 women with a normotensive first pregnancy; 1092 with preeclampsia, and 478 with gestational hypertension in first pregnancy. Already before first pregnancy, women with preeclampsia in their first pregnancy had higher measures of adiposity, blood pressure, heart rate, and serum lipids and glucose compared with women with a normotensive first pregnancy. After first pregnancy, there was a parallel development in cardiovascular risk factor levels, but women with a normotensive first pregnancy had a time lag of >10 years compared with the preeclampsia group. There were no clear differences in risk factor trajectories between women with gestational hypertension and women with preeclampsia. Conclusions Women with hypertensive pregnancy disorders in their first pregnancy had an adverse cardiovascular risk factor profile before pregnancy compared with normotensive women, and the differences persisted beyond 50 years of age. Hypertensive disorders in pregnancy signal long-term increases in modifiable cardiovascular risk factors, and may be used to identify women who would benefit from early prevention strategies.


Immunohistochemical evidence of disease recurrence after liver transplantation for primary biliary cirrhosis.
Whether primary biliary cirrhosis (PBC) recurs after liver transplantation has remained an interesting and controversial issue; rejection, viral hepatitis, and drug effects all may mimic recurrent PBC histologically and biochemically. Furthermore, reliable clinical criteria for PBC recurrence are lacking. In this study, the issue of disease recurrence using a well-characterized monoclonal antibody (MAb), C355.1, that reacts with the immunodominant mitochondrial autoantigen of PBC (pyruvate dehydrogenase complex [PDC-E2]) was addressed. When used in an immunohistochemical assay, C355.1 produces intense apical staining of bile duct epithelium specifically in liver sections of patients with PBC and may be the earliest known marker of PBC. Immunohistochemical and histological analysis of serial liver biopsy specimens of 67 patients pre- and post-orthotopic liver transplantation (OLT), including 38 patients with PBC and 29 non-PBC liver disease controls, was performed. Sections were stained with MAb C355.1 or the control MAb C315 and analyzed to determine whether there was a recurrence of apical reactivity in the bile ducts of the posttransplantation biopsy specimens. The immunohistochemical staining was correlated with the histological findings and serum biochemistries at the time of the biopsy. Our data indicate that a significant number of patients who underwent transplantation for PBC (28 of 38) but not controls (0 of 29) develop a staining pattern of liver bile duct epithelium with MAb C355.1 that is indistinguishable from the pretransplantation pattern. Of the 28 patients with this apical staining pattern, 8 were characterized histologically as possible recurrent PBC, 2 as chronic rejection, 2 as acute rejection, 9 as nonspecific changes, 4 as normal or near normal, and 3 had other histological changes. Only 50% of the patients with apical C355.1 staining had liver enzyme levels suggestive of cholestasis. Thus, there appears to be immunohistochemical evidence that supports the concept of recurrence of PBC after OLT. The appearance of biliary epithelial abnormalities before the clinical appearance of disease is important not only for liver transplantation but also for understanding the natural history of PBC.


Genome Sequence Analysis of CsRV1: A Pathogenic Reovirus that Infects the Blue Crab Callinectes sapidus Across Its Trans-Hemispheric Range.
The blue crab, Callinectes sapidus Rathbun, 1896, which is a commercially important trophic link in coastal ecosystems of the western Atlantic, is infected in both North and South America by C. sapidus Reovirus 1 (CsRV1), a double stranded RNA virus. The 12 genome segments of a North American strain of CsRV1 were sequenced using Ion Torrent technology. Putative functions could be assigned for 3 of the 13 proteins encoded in the genome, based on their similarity to proteins encoded in other reovirus genomes. Comparison of the CsRV1 RNA-dependent RNA polymerase (RdRP) sequence to genomes of other crab-infecting reoviruses shows that it is similar to the mud crab reovirus found in Scylla serrata and WX-2012 in Eriocheir sinensis, Chinese mitten crab, and supports the idea that there is a distinct "Crabreo" genus, different from Seadornavirus and Cardoreovirus, the two closest genera in the Reoviridae. A region of 98% nucleotide sequence identity between CsRV1 and the only available sequence of the P virus of Macropipus depurator suggests that these two viruses may be closely related. An 860 nucleotide region of the CsRV1 RdRP gene was amplified and sequenced from 15 infected crabs collected from across the geographic range of C. sapidus. Pairwise analysis of predicted protein sequences shows that CsRV1 strains in Brazil can be distinguished from those in North America based on conserved residues in this gene. The sequencing, annotation, and preliminary population metrics of the genome of CsRV1 should facilitate additional studies in diverse disciplines, including structure-function relationships of reovirus proteins, investigations into the evolution of the Reoviridae, and biogeographic research on the connectivity of C. sapidus populations across the Northern and Southern hemispheres.


Parallel effects of genetic variation in ACE activity in baboons and humans.
Like humans, savannah baboons (Papio sp.) show heritable interindividual variation in complex physiological phenotypes. One prominent example of such variation involves production of the homeostatic regulator protein angiotensin converting enzyme (ACE), which shows heritable variation in both baboons and humans. In humans, this phenotypic variation is associated with an Alu insertion-deletion polymorphism in the ACE gene, which explains approximately half of the variation in serum ACE activity. We identified a similar Alu insertion-deletion polymorphism in the baboon ACE homologue and measured its frequency in a wild population and a captive population of baboons. We also analyzed the contribution of ACE genotype at this indel to variation in serum ACE activity in the captive population. When conditioned on weight, a known factor affecting ACE activity in humans, age and ACE genotype both accounted for variance in ACE activity; in particular, we identified a significant nonadditive interaction between age and genotype. A model incorporating this interaction effect explained 21.6% of the variation in residual serum ACE activity. Individuals homozygous for the deletion mutation exhibited significantly higher levels of ACE activity than insertion-deletion heterozygotes at younger ages (10-14 years), but showed a trend towards lower levels of ACE activity compared with heterozygotes at older ages (> or =15 years). These results demonstrate an interesting parallel between the genetic architecture underlying ACE variation in humans and baboons, suggesting that further attention should be paid in humans to the relationship between ACE genetic variation and aging.


Paneth cells as a site of origin for intestinal inflammation.
The recognition of autophagy related 16-like 1 (ATG16L1) as a genetic risk factor has exposed the critical role of autophagy in Crohn's disease. Homozygosity for the highly prevalent ATG16L1 risk allele, or murine hypomorphic (HM) activity, causes Paneth cell dysfunction. As Atg16l1(HM) mice do not develop spontaneous intestinal inflammation, the mechanism(s) by which ATG16L1 contributes to disease remains obscure. Deletion of the unfolded protein response (UPR) transcription factor X-box binding protein-1 (Xbp1) in intestinal epithelial cells, the human orthologue of which harbours rare inflammatory bowel disease risk variants, results in endoplasmic reticulum (ER) stress, Paneth cell impairment and spontaneous enteritis. Unresolved ER stress is a common feature of inflammatory bowel disease epithelium, and several genetic risk factors of Crohn's disease affect Paneth cells. Here we show that impairment in either UPR (Xbp1(ΔIEC)) or autophagy function (Atg16l1(ΔIEC) or Atg7(ΔIEC)) in intestinal epithelial cells results in each other's compensatory engagement, and severe spontaneous Crohn's-disease-like transmural ileitis if both mechanisms are compromised. Xbp1(ΔIEC) mice show autophagosome formation in hypomorphic Paneth cells, which is linked to ER stress via protein kinase RNA-like endoplasmic reticulum kinase (PERK), elongation initiation factor 2α (eIF2α) and activating transcription factor 4 (ATF4). Ileitis is dependent on commensal microbiota and derives from increased intestinal epithelial cell death, inositol requiring enzyme 1α (IRE1α)-regulated NF-κB activation and tumour-necrosis factor signalling, which are synergistically increased when autophagy is deficient. ATG16L1 restrains IRE1α activity, and augmentation of autophagy in intestinal epithelial cells ameliorates ER stress-induced intestinal inflammation and eases NF-κB overactivation and intestinal epithelial cell death. ER stress, autophagy induction and spontaneous ileitis emerge from Paneth-cell-specific deletion of Xbp1. Genetically and environmentally controlled UPR function within Paneth cells may therefore set the threshold for the development of intestinal inflammation upon hypomorphic ATG16L1 function and implicate ileal Crohn's disease as a specific disorder of Paneth cells.


Melanocyte biology and function with reference to oral melanin hyperpigmentation in HIV-seropositive subjects.
The color of normal skin and of oral mucosa is not determined by the number of melanocytes in the epithelium but rather by their melanogenic activity. Pigmented biopolymers or melanins are synthesized in melanosomes. Tyrosinase is the critical enzyme in the biosynthesis of both brown/black eumelanin and yellow/red pheomelanin. The number of the melanosomes within the melanocytes, the type of melanin within the melanosomes, and the efficacy of the transfer of melanosomes from the melanocytes to the neighboring keratinocytes all play an important role in tissue pigmentation. Melanin production is regulated by locally produced factors including proopiomelanocortin and its derivative peptides, particularly alpha-melanocyte-stimulating hormone (α-MSH), melanocortin 1 receptor (MC1R), adrenergic and cholinergic agents, growth factors, cytokines, and nitric oxide. Both eumelanin and pheomelanin can be produced by the same melanocytes, and the proportion of the two melanin types is influenced by the degree of functional activity of the α-MSH/MC1R intracellular pathway. The cause of HIV oral melanosis is not fully understood but may be associated with HIV-induced cytokine dysregulation, with the medications commonly prescribed to HIV-seropositive persons, and with adrenocortical dysfunction, which is not uncommon in HIV-seropositive subjects with AIDS. The purpose of this article is to discuss some aspects of melanocyte biology and HIV-associated oral melanin hyperpigmentation.


Silencing of the IKKε gene by siRNA inhibits invasiveness and growth of breast cancer cells.
IκB Kinase ε (IKKε) is a member of the IKK family which plays an important role in the activation of nuclear factor-κB (NF-κB). Overexpressed in over 30% of breast cancers, IKKε has been recently identified as a potential breast cancer oncogene. The purpose of this study is to examine the therapeutic potential of IKKε siRNA on human breast cancer cells. Eight siRNAs targeting different regions of the IKKε mRNA were designed, and the silencing effect was screened by quantitative real time RT-PCR. The biological effects of synthetic siRNAs on human breast cancer cells were investigated by examining the cell proliferation, migration, invasion, focus formation, anchorage-independent growth(via soft agar assay), cell cycle arrest, apoptosis (via annexing binding), NF-κB basal level, and NF-κB related gene expressions upon the IKKε silencing. Silencing of IKKε in human breast cancer cells resulted in decrease of focus formation potential and clonogenicity as well as in vitro cell migration/invasion capabilities. Moreover, knockdown of IKKε suppressed cell proliferation. Cell cycle assay showed that the anti-proliferation effect of IKKε siRNA was mediated by arresting cells in G(0)/G(1) phase, which was caused by down-regulation of cyclin D(1). Furthermore, we demonstrated that silencing of IKKε inhibited the NF-κB basal activity as well as the Bcl-2 expression. Significant apoptosis was not observed in breast cancer cells upon the silencing of IKKε. The present study provided the first evidence that silencing IKKε using synthetic siRNA could inhibit the invasiveness properties and proliferation of breast cancer cells. Our results suggested that silencing IKKε using synthetic siRNA may offer a novel therapeutic strategy for breast cancer.


Efficacy of computerized tomography in the preoperative staging of pancreatic carcinoma.
The increasing use of nonoperative methods for the diagnosis and palliative treatment of pancreatic cancer has placed greater emphasis on computerized tomography (CT) in staging of this malignancy. The present study was done to review our experience with CT in staging pancreatic cancer, specifically its efficacy in predicting lesions amenable to curative versus noncurative surgical treatment. Sixty six consecutive patients with pancreatic cancer who were considered potential candidates for surgical resection and who had preoperative CT scans over the 4-year period from 1982 through 1986 were studied. Preoperative CT scans were reviewed by a radiologist without knowledge of patients' surgical management. CT criteria for unresectable disease include hepatic and distant metastasis as well as evidence of locally advanced disease, including peripancreatic fascial extension, extension of tumor to locally contiguous structures, vascular encasement/invasion, and local lymphadenopathy. CT predicted resectability with a sensitivity of 75 per cent and a positive predictive value of 38 per cent. Unresectability was predicted with a sensitivity of 72 per cent and positive predictive value of 93 per cent. CT incorrectly predicted unresectable disease in three patients who had a curative resection. CT was most reliable when it predicted unresectability due to the presence of hepatic and/or distant metastasis. CT predicted unresectability with least sensitivity using criteria for locally advanced disease. Therapeutic decisions for nonoperative management of patients with pancreatic cancer based upon CT predictions of unresectable disease, especially predictions of unresectability solely on the basis of locally advanced disease, can not be recommended at this time.


Memory T cells established by seasonal human influenza A infection cross-react with avian influenza A (H5N1) in healthy individuals.
The threat of avian influenza A (H5N1) infection in humans remains a global health concern. Current influenza vaccines stimulate antibody responses against the surface glycoproteins but are ineffective against strains that have undergone significant antigenic variation. An alternative approach is to stimulate pre-existing memory T cells established by seasonal human influenza A infection that could cross-react with H5N1 by targeting highly conserved internal proteins. To determine how common cross-reactive T cells are, we performed a comprehensive ex vivo analysis of cross-reactive CD4+ and CD8+ memory T cell responses to overlapping peptides spanning the full proteome of influenza A/Viet Nam/CL26/2005 (H5N1) and influenza A/New York/232/2004 (H3N2) in healthy individuals from the United Kingdom and Viet Nam. Memory CD4+ and CD8+ T cells isolated from the majority of participants exhibited human influenza-specific responses and showed cross-recognition of at least one H5N1 internal protein. Participant CD4+ and CD8+ T cells recognized multiple synthesized influenza peptides, including peptides from the H5N1 strain. Matrix protein 1 (M1) and nucleoprotein (NP) were the immunodominant targets of cross-recognition. In addition, cross-reactive CD4+ and CD8+ T cells recognized target cells infected with recombinant vaccinia viruses expressing either H5N1 M1 or NP. Thus, vaccine formulas inducing heterosubtypic T cell-mediated immunity may confer broad protection against avian and human influenza A viruses.


Levalbuterol aerosol delivery with a nonelectrostatic versus a nonconducting valved holding chamber.
Hydrofluoroalkane-propelled levalbuterol (Xopenex) aerosol is a recently approved formulation for delivery via metered-dose inhaler for the treatment or prevention of bronchospasm in adults, adolescents, and children > or = 4 years of age who have reversible obstructive airway disease. Valved holding chambers (VHCs) made from conventional polymers are susceptible to accumulation of electrostatic charge, which can be minimized by prewashing with ionic detergent, but it may be desirable to be able to use the product straight from the package, without pretreatment, especially during an exacerbation. We studied the performance of the AeroChamber Plus and AeroChamber Max VHCs in delivering hydrofluoroalkane-propelled levalbuterol. Both VHCs were prewashed, rinsed, and drip-dried before testing. The AeroChamber Max is manufactured from charge-dissipative material and was therefore also evaluated without prewashing. Aerosol samples were collected at 28.3 L/min with an Andersen 8-stage cascade impactor, per the procedure specified in Chapter 601 of the United States Pharmacopeia. The mean +/- SD fine-particle mass (mass of aerosol particles < 4.7 microm aerodynamic diameter) values were 33.5 +/- 1.4 microg and 36.3 +/- 1.1 microg with the AeroChamber Max, without and with wash/rinse pretreatment, respectively, and 28.5 +/- 2.4 microg with the prewashed AeroChamber Plus. We think the small differences we observed are unlikely to be of clinical importance, given the inter-patient variability seen with inhaled drug delivery. The performance of the AeroChamber Max was substantially comparable whether or not it was prewashed.


Cancer stem cells and exosome signaling.
Exosomes have been recognized as mediators of intercellular communication among different cell populations in various biological model systems. By transfer of signaling molecules such as proteins, lipids, and RNAs between different cell types, exosomes are implicated in both physiological and pathological processes. The tumor microenvironment consists of multiple types of cells including adult stem cells, cancer stem cells, and stromal cells. These cells are known to intercommunicate with each other thereby modulating tumor progression. Recent studies have provided evidence demonstrating that exosomes mediate the interactions among different types of cells within the tumor microenvironment, providing new insight into how these cells interact with each other through exosome signaling. This review is focused on recent studies that have examined exosome-mediated intercommunication among cancer stem cells, adult stem cells, cancer cells, and stromal cells within the tumor microenvironment. Based on the current literature, it seems clear that adult stem cells and cancer stem cells secret exosomes that can be transferred to their surrounding cells thereby modulating cancer progression. Likewise, cancer cells and stromal cells also release exosomes that can be taken up by cancer stem cells or adult stem cells, leading to alterations to their phenotype. The molecular mechanisms and biological consequences of the exosome-mediated interactions of these cells remain to be further elucidated. A better understanding of how exosomes mediate intercellular communication in the tumor microenvironment and the specific biological consequences of these interactions will likely offer new opportunities in the development of diagnostic or therapeutic strategies against cancer.


Psychosocial precursors of hypertension: a review of the epidemiologic evidence.
This article provides a selective overview of epidemiologic studies on the relationship between psychosocial factors and blood pressure elevation. The review focuses on English-language reports published since 1975 and emphasizes two broad areas of research: changes in mean blood pressures of third world populations undergoing modernization, and psychosocial correlates of elevated blood pressure in low socioeconomic status (SES) and black populations within the continental United States. The recent modernization studies provide additional evidence that rapid sociocultural change is associated with increased prevalence of hypertension. To account for these effects, several studies have advanced the general thesis that modernization impacts traditional value systems of third world populations in ways that frequently engender discrepancies between their newly acquired aspirations for a Western lifestyle and their socioeconomic resources to successfully pursue that lifestyle. There is overlap between this formulation and recent investigations of hypertension in low SES and black populations in the United States. The report concludes with a discussion of epidemiologic studies of anger and hypertension, emphasizing some of the complexities that characterize this area of research.


Automatic categorization of diverse experimental information in the bioscience literature.
Curation of information from bioscience literature into biological knowledge databases is a crucial way of capturing experimental information in a computable form. During the biocuration process, a critical first step is to identify from all published literature the papers that contain results for a specific data type the curator is interested in annotating. This step normally requires curators to manually examine many papers to ascertain which few contain information of interest and thus, is usually time consuming. We developed an automatic method for identifying papers containing these curation data types among a large pool of published scientific papers based on the machine learning method Support Vector Machine (SVM). This classification system is completely automatic and can be readily applied to diverse experimental data types. It has been in use in production for automatic categorization of 10 different experimental datatypes in the biocuration process at WormBase for the past two years and it is in the process of being adopted in the biocuration process at FlyBase and the Saccharomyces Genome Database (SGD). We anticipate that this method can be readily adopted by various databases in the biocuration community and thereby greatly reducing time spent on an otherwise laborious and demanding task. We also developed a simple, readily automated procedure to utilize training papers of similar data types from different bodies of literature such as C. elegans and D. melanogaster to identify papers with any of these data types for a single database. This approach has great significance because for some data types, especially those of low occurrence, a single corpus often does not have enough training papers to achieve satisfactory performance. We successfully tested the method on ten data types from WormBase, fifteen data types from FlyBase and three data types from Mouse Genomics Informatics (MGI). It is being used in the curation work flow at WormBase for automatic association of newly published papers with ten data types including RNAi, antibody, phenotype, gene regulation, mutant allele sequence, gene expression, gene product interaction, overexpression phenotype, gene interaction, and gene structure correction. Our methods are applicable to a variety of data types with training set containing several hundreds to a few thousand documents. It is completely automatic and, thus can be readily incorporated to different workflow at different literature-based databases. We believe that the work presented here can contribute greatly to the tremendous task of automating the important yet labor-intensive biocuration effort.


Radiofrequency electromagnetic fields do not alter the cell cycle progression of C3H 10T and U87MG cells.
The effects of exposure to radiofrequency electromagnetic fields (RF EMFs) on cell cycle progression of mouse fibroblasts C3H 10T(1/2) and human glioma U87MG cells were determined by the flow cytometric bromodeoxyuridine pulse-chase method. Cells were exposed to a frequency-modulated continuous wave at 835.62 MHz or a code division multiple access RF EMF centered on 847.74 MHz at an average specific absorption rate of 0.6 W/kg. Five cell cycle parameters, including the transit of cells through G(1), G(2) and S phase and the probability of cell division, were examined immediately after the cells were placed in the fields or after they had been kept in the fields for up to 100 h. The only significant change observed in the study was that associated with C3H 10T(1/2) cell cultures moving into plateau phase toward the later times in the long-exposure experiment. No changes in the cell cycle parameters were observed in cells exposed to either mode of RF EMFs when compared to sham-exposed cells in either of the cell lines studied during the entire experimental period. The results show that exposure to RF EMFs, at the frequencies and power tested, does not have any effect on cell progression in vitro.


Development of the choroid plexus.
Mammalian choroid plexuses develop at four sites in the roof of the neural tube shortly after its closure, in the order IVth, lateral, and IIIrd ventricles. Bone morphogenetic proteins and tropomyosin are involved in early specification of these sites and in early plexus growth. Four stages of lateral ventricular plexus development have been defined, based on human and sheep fetuses; these depend mainly on the appearance of epithelial cells and presence or absence of glycogen. Other plexuses and other species are probably similar, although marsupials may lack glycogen. Choroid plexuses form one of the blood-brain barrier interfaces that control the brain's internal environment. The mechanisms involved combine a structural diffusion restraint (tight junctions between the plexus epithelial cells) and specific exchange mechanisms. In this review, it is argued that barrier mechanisms in the developing brain are different in important respects from those in the adult brain, but these differences do not necessarily reflect immaturity of the system. Absence of a barrier mechanism or presence of one not found in the adult may be a specialisation that is appropriate for that stage of brain development. Emphasis is placed on determining which mechanisms are present in the immature brain and relating them to brain development. One mechanism unique to the developing brain transfers specific proteins from blood to cerebrospinal fluid (CSF), via tubulocisternal endoplasmic reticulum in plexus epithelial cells. This results in a high concentration of proteins in early CSF. These proteins do not penetrate into brain extracellular space because of "strap" junctions between adjacent neuroependymal cells, which disappear later in development, when the protein concentration in CSF is much lower. Functions of the proteins in early CSF are discussed in terms of generation of a "colloid" osmotic pressure that expands the ventricular system as the brain grows; the proteins may also act as specific carriers and growth factors in their own right. The pathway for low molecular weight compounds, which is much more permeable in the developing choroid plexuses, appears also to be a transcellular one, rather than paracellular via tight junctions. There is thus good evidence to support a novel view of the state of development and functional significance of barrier mechanisms in the immature brain. It grows in an environment that is different from that of the rest of the fetus/neonate and that is also different in some respects from that of the adult. But these differences reflect developmental specialisation rather than immaturity.


Glucose starvation boosts Entamoeba histolytica virulence.
The unicellular parasite, Entamoeba histolytica, is exposed to numerous adverse conditions, such as nutrient deprivation, during its life cycle stages in the human host. In the present study, we examined whether the parasite virulence could be influenced by glucose starvation (GS). The migratory behaviour of the parasite and its capability to kill mammalian cells and to lyse erythrocytes is strongly enhanced following GS. In order to gain insights into the mechanism underlying the GS boosting effects on virulence, we analyzed differences in protein expression levels in control and glucose-starved trophozoites, by quantitative proteomic analysis. We observed that upstream regulatory element 3-binding protein (URE3-BP), a transcription factor that modulates E.histolytica virulence, and the lysine-rich protein 1 (KRiP1) which is induced during liver abscess development, are upregulated by GS. We also analyzed E. histolytica membrane fractions and noticed that the Gal/GalNAc lectin light subunit LgL1 is up-regulated by GS. Surprisingly, amoebapore A (Ap-A) and cysteine proteinase A5 (CP-A5), two important E. histolytica virulence factors, were strongly down-regulated by GS. While the boosting effect of GS on E. histolytica virulence was conserved in strains silenced for Ap-A and CP-A5, it was lost in LgL1 and in KRiP1 down-regulated strains. These data emphasize the unexpected role of GS in the modulation of E.histolytica virulence and the involvement of KRiP1 and Lgl1 in this phenomenon.


Fast and slow light in zigzag microring resonator chains.
We analyze fast- and slow-light transmission in a zigzag microring resonator chain. In the superluminal case, a new light-transmission effect is found whereby the input optical pulse is reproduced in an almost-simultaneous manner at the various system outputs. When the input carrier is tuned to a different frequency, the system permits to slow down the propagating optical signal. Between these two extreme cases, the relative delay can be tuned within a broad range. We propose, and analyze numerically, a laser-array configuration for the stable operation of active devices.


The effects of high-dose heparin on inflammatory and coagulation parameters following cardiopulmonary bypass.
Systemic inflammation and the activation of the coagulation system following cardiopulmonary bypass (CPB) may contribute to postoperative complications. In vitro studies have demonstrated that heparin possesses anti-inflammatory properties. To ascertain the relative benefits of high versus low heparin doses, we studied the impact of varying heparin doses on the inflammatory response and coagulation system during and following CPB. Forty patients scheduled for elective coronary artery bypass surgery requiring CPB were randomized to either a low dose (300 U/kg) (Group L) or a high dose of unfractionated heparin (600 U/kg) (Group H). To evaluate the inflammatory response, proinflammatory cytokines [tumor necrosis factor-alpha and interleukin-6 (IL-6)] were measured at four different times: before CPB (T0), 30 min after the institution of CPB (T1), 30 min after cross-clamp release (T2), and 4 h after the end of CPB (T3). Thrombin-antithrombin complex, platelet factor 4 and anti-activated factor X heparin concentrations were also measured. Patients in Group H received greater heparin (44.934 U versus 27.741 U, P<0.001) and protamine (P=0.003) doses. Postoperative blood loss and blood products transfusions were not significantly different in the groups. At T1, mean heparin plasma concentration was higher in Group H (P<0.001). IL-6 was significantly lower in Group H compared with Group L (P=0.01) only at T1. Using a mixed-effects statistical model, tumor necrosis factor-alpha and IL-6 levels were comparable regardless of the heparin dose. Thrombin-antithrombin complex levels were lower in Group H (P=0.04) and platelet factor 4 levels were significantly lower in Group H at T2 (P=0.04). Higher heparin doses were associated with higher heparin concentrations during CPB. A high heparin dose achieved a better preservation of the coagulation system with less thrombin formation and platelet activation. The heparin dose had small influence on proinflammatory cytokines release.


Two Decades of Invasive Western Corn Rootworm Population Monitoring in Croatia.
Western corn rootworm (WCR) is the worst pest of maize in the United States, and since its spread through Europe, WCR is now recognized as the most serious pest affecting maize production. After the beetle's first detection in Serbia in 1992, neighboring countries such as Croatia have established a national monitoring program. For more than two decades WCR adult population abundance and variability was monitored. With traditional density monitoring, more recent genetic monitoring, and the newest morphometric monitoring of WCR populations, Croatia possesses a great deal of knowledge about the beetle's invasion process over time and space. Croatia's position in Europe is unique as no other European nation has demonstrated such a detailed and complete understanding of an invasive insect. The combined use of traditional monitoring (attractant cards), which can be effectively used to predict population abundance, and modern monitoring procedures, such as population genetics and geometric morphometrics, has been effectively used to estimate inter- and intra-population variation. The combined application of traditional and modern monitoring techniques will enable more efficient control and management of WCR across Europe. This review summarizes the research on WCR in Croatia from when it was first detected in 1992 until 2018. An outline of future research needs is provided.


Characterization of the image-derived carotid artery input function using independent component analysis for the quantitation of [18F] fluorodeoxyglucose positron emission tomography images.
We previously developed a noninvasive technique for the quantification of fluorodeoxyglucose (FDG) positron emission tomography (PET) images using an image-derived input function obtained from a manually drawn carotid artery region. Here, we investigate the use of independent component analysis (ICA) for more objective identification of the carotid artery and surrounding tissue regions. Using FDG PET data from 22 subjects, ICA was applied to an easily defined cubical region including the carotid artery and neighboring tissue. Carotid artery and tissue time activity curves and three venous samples were used to generate spillover and partial volume-corrected input functions and to calculate the parametric images of the cerebral metabolic rate for glucose (CMRgl). Different from a blood-sampling-free ICA approach, the results from our ICA approach are numerically well matched to those based on the arterial blood sampled input function. In fact, the ICA-derived input functions and CMRgl measurements were not only highly correlated (correlation coefficients >0.99) to, but also highly comparable (regression slopes between 0.92 and 1.09), with those generated using arterial blood sampling. Moreover, the reliability of the ICA-derived input function remained high despite variations in the location and size of the cubical region. The ICA procedure makes it possible to quantify FDG PET images in an objective and reproducible manner.


Use of radiopharmaceuticals in diagnostic nuclear medicine in the United States: 1960-2010.
To reconstruct reliable nuclear medicine-related occupational radiation doses or doses received as patients from radiopharmaceuticals over the last five decades, the authors assessed which radiopharmaceuticals were used in different time periods, their relative frequency of use, and typical values of the administered activity. This paper presents data on the changing patterns of clinical use of radiopharmaceuticals and documents the range of activity administered to adult patients undergoing diagnostic nuclear medicine procedures in the U.S. between 1960 and 2010. Data are presented for 15 diagnostic imaging procedures that include thyroid scan and thyroid uptake; brain scan; brain blood flow; lung perfusion and ventilation; bone, liver, hepatobiliary, bone marrow, pancreas, and kidney scans; cardiac imaging procedures; tumor localization studies; localization of gastrointestinal bleeding; and non-imaging studies of blood volume and iron metabolism. Data on the relative use of radiopharmaceuticals were collected using key informant interviews and comprehensive literature reviews of typical administered activities of these diagnostic nuclear medicine studies. Responses of key informants on relative use of radiopharmaceuticals are in agreement with published literature. Results of this study will be used for retrospective reconstruction of occupational and personal medical radiation doses from diagnostic radiopharmaceuticals to members of the U.S. radiologic technologists' cohort and in reconstructing radiation doses from occupational or patient radiation exposures to other U.S. workers or patient populations.


Timeliness and risk factors associated with delay for pneumococcal conjugate 10-valent routine immunization in Brazilian children.
Vaccination coverage is the usual metrics to evaluate the immunization programs performance. For the 10-valent pneumococcal conjugate (PCV10) vaccine, measuring the delay of vaccination is also important, particularly as younger children are at increased risk of disease. Routinely collected administrative data was used to assess the timeliness of PCV10 vaccination, and the factors associated with delay to receive the first and second doses, and the completion of the PCV10 3+1 schedule. A population-based retrospective cohort study was conducted with children born in 2012 in Central Brazil. Children who received the PCV10 first dose in public health services were followed-up until 23months of age. Timeliness of receiving each PCV10 dose at any given age was defined as receiving the dose within 28days grace period from the recommended age by the National Immunization Program. Log-binomial regression models were used to examine risk factors for delays of the first dose and the completion PCV10 3+1 schedule. In total, 14,282 children were included in the cohort of study. Delayed vaccination occurred in 9.4%, 23.8%, 36.8% and 39.9% children for the first, second, third and the booster doses, respectively. A total of 1912 children (12.8% of the cohort) were not adequately vaccinated at the 6months of life; 1,071 (7%) received the second dose after 6months of age, 784 (5.4%) did not receive the second dose, and 57 (0.4%) received the first dose after six months of life. A considerable delay was found in PCV10 third and booster doses. Almost 2 thousand children had not received the recommended PCV10 doses at 6months of age. Timeliness of vaccination is an issue in Brazil although high vaccination coverages.


The national portfolio for postgraduate family medicine training in South Africa: a descriptive study of acceptability, educational impact, and usefulness for assessment.
Since 2007 a portfolio of learning has become a requirement for assessment of postgraduate family medicine training by the Colleges of Medicine of South Africa. A uniform portfolio of learning has been developed and content validity established among the eight postgraduate programmes. The aim of this study was to investigate the portfolio's acceptability, educational impact, and perceived usefulness for assessment of competence. Two structured questionnaires of 35 closed and open-ended questions were delivered to 53 family physician supervisors and 48 registrars who had used the portfolio. Categorical and nominal/ordinal data were analysed using simple descriptive statistics. The open-ended questions were analysed with ATLAS.ti software. Half of registrars did not find the portfolio clear, practical or feasible. Workshops on portfolio use, learning, and supervision were supported, and brief dedicated time daily for reflection and writing. Most supervisors felt the portfolio reflected an accurate picture of learning, but just over half of registrars agreed. While the portfolio helped with reflection on learning, participants were less convinced about how it helped them plan further learning. Supervisors graded most rotations, suggesting understanding the summative aspect, while only 61% of registrars reflected on rotations, suggesting the formative aspects are not yet optimally utilised. Poor feedback, the need for protected academic time, and pressure of service delivery impacting negatively on learning. This first introduction of a national portfolio for postgraduate training in family medicine in South Africa faces challenges similar to those in other countries. Acceptability of the portfolio relates to a clear purpose and guide, flexible format with tools available in the workplace, and appreciating the changing educational environment from university-based to national assessments. The role of the supervisor in direct observations of the registrar and dedicated educational meetings, giving feedback and support, cannot be overemphasized.


Model-Based Comprehensive Analysis of School Closure Policies for Mitigating Influenza Epidemics and Pandemics.
School closure policies are among the non-pharmaceutical measures taken into consideration to mitigate influenza epidemics and pandemics spread. However, a systematic review of the effectiveness of alternative closure policies has yet to emerge. Here we perform a model-based analysis of four types of school closure, ranging from the nationwide closure of all schools at the same time to reactive gradual closure, starting from class-by-class, then grades and finally the whole school. We consider policies based on triggers that are feasible to monitor, such as school absenteeism and national ILI surveillance system. We found that, under specific constraints on the average number of weeks lost per student, reactive school-by-school, gradual, and county-wide closure give comparable outcomes in terms of optimal infection attack rate reduction, peak incidence reduction or peak delay. Optimal implementations generally require short closures of one week each; this duration is long enough to break the transmission chain without leading to unnecessarily long periods of class interruption. Moreover, we found that gradual and county closures may be slightly more easily applicable in practice as they are less sensitive to the value of the excess absenteeism threshold triggering the start of the intervention. These findings suggest that policy makers could consider school closure policies more diffusely as response strategy to influenza epidemics and pandemics, and the fact that some countries already have some experience of gradual or regional closures for seasonal influenza outbreaks demonstrates that logistic and feasibility challenges of school closure strategies can be to some extent overcome.


Does a Self-etching Ceramic Primer Improve Bonding to Lithium Disilicate Ceramics? Bond Strengths and FESEM Analyses.
To compare the effect of hydrofluoric acid (HF) vs self-etching ceramic primer on resin cement microshear bond strength (μSBS) and ultramorphology of lithium disilicate (LD) ceramic. LD (IPS e.max CAD, Ivoclar Vivadent) blocks (14×4×2 mm3) were polished to 1200 grit and assigned to nine groups (n=5): CON: control, no LD surface treatment; IVO: 5.0% HF (IPS Ceramic Etching Gel, Ivoclar Vivadent); VIT: 5.0% HF (Vita Ceramics Etch, VITA Zahnfabrik); FGM: 5.0% HF (Condac Porcelana, FGM); ULT: 9.0% HF (Porcelain Etch, Ultradent); PRM: 9.6% HF (Premier Porcelain Etch Gel, Premier); BIS: 9.5% HF (Porcelain Etchant, Bisco Inc); DEN: 10.0% HF (Condicionador de Porcelanas, Dentsply Brazil); and MEP: self-etching ceramic primer (Monobond Etch & Prime, Ivoclar Vivadent). For all HF groups and control, an MDP-containing silane solution (MB+, Monobond Plus, Ivoclar Vivadent) was applied on rinsing the HF gel and air drying. Three transparent matrices for each specimen were filled with light-cured resin cement (Variolink Veneer, Ivoclar Vivadent). After storage in water for 48 hours at 37°C, specimens were tested in shear mode to measure μSBS. Mode of failure was analyzed at 50×. Statistical analysis included one-way analysis of variance and the Duncan post hoc test (α=0.05). Thirty-six additional LD specimens were assigned to the same experimental groups (n=4) and observed under a field-emission scanning electron microscope (FESEM) at magnifications ranging from 10,000× to 100,000×. IVO resulted in statistically higher mean μSBS than all the other groups. MEP resulted in statistically lower μSBS than all HF groups. The failure mode for MEP was predominantly adhesive. The most frequent failure mode for the HF groups was mixed. CON resulted in 100% pretesting failures. For FESEM, no retentive pattern was observed for CON specimens. MEP resulted in the least pronounced etching pattern, few areas around crystals exhibited a slight increase in retention pattern compared to the control group. All HF gels created microporosities on the LD surface with distinct etching patterns. VIT and DEN resulted in an LD ultramorphology that suggested overetching. HF etching followed by a silane solution resulted in higher bond strengths than a self-etching ceramic primer. Some HF gels may cause overetching of the LD intaglio surface.


Infection with transmissible strains of Pseudomonas aeruginosa and clinical outcomes in adults with cystic fibrosis.
Studies from Australia and the United Kingdom have shown that some patients with cystic fibrosis are infected with common transmissible strains of Pseudomonas aeruginosa. To determine the prevalence and incidence of infection with transmissible strains of P. aeruginosa and whether presence of the organism was associated with adverse clinical outcomes in Canada. Prospective observational cohort study of adult patients cared for at cystic fibrosis clinics in Ontario, Canada, with enrollment from September 2005 to September 2008. Sputum was collected at baseline, 3 months, and yearly thereafter for 3 years; and retrieved P. aeruginosa isolates were genotyped. Vital status (death or lung transplant) was assessed for all enrolled patients until December 31, 2009. Incidence and prevalence of P. aeruginosa isolation, rates of decline in lung function, and time to death or lung transplantation. Of the 446 patients with cystic fibrosis studied, 102 were discovered to be infected with 1 of 2 common transmissible strains of P. aeruginosa at study entry. Sixty-seven patients were infected with strain A (15%), 32 were infected with strain B (7%), and 3 were simultaneously infected with both strains (0.6%). Strain A was found to be genetically identical to the Liverpool epidemic strain but strain B has not been previously described as an epidemic strain. The incidence rate of new infections with these 2 transmissible strains was relatively low (7.0 per 1000 person-years; 95% confidence interval [CI], 1.8-12.2 per 1000 person-years). Compared with patients infected with unique strains of P. aeruginosa, patients infected with the Liverpool epidemic strain (strain A) and strain B had similar declines in lung function (difference in decline in percent predicted forced expiratory volume in the first second of expiration of 0.64% per year [95% CI, -1.52% to 2.80% per year] and 1.66% per year [95% CI, -1.00% to 4.30%], respectively). However, the 3-year rate of death or lung transplantation was greater in those infected with the Liverpool epidemic strain (18.6%) compared with those infected with unique strains (8.7%) (adjusted hazard ratio, 3.26 [95% CI, 1.41 to 7.54]; P = .01). A common strain of P. aeruginosa (Liverpool epidemic strain/strain A) infects patients with cystic fibrosis in Canada and the United Kingdom. Infection with this strain in adult Canadian patients with cystic fibrosis was associated with a greater risk of death or lung transplantation.


Differential activation of peroxisome proliferator-activated receptor-gamma by troglitazone and rosiglitazone.
The antidiabetic thiazolidinediones, which include troglitazone and rosiglitazone, are ligands for the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-gamma and exert their antihyperglycemic effects by regulation of PPAR-gamma-responsive genes. We report here that PPAR-gamma activation by troglitazone depends on the experimental setting. Troglitazone acts as a partial agonist for PPAR-gamma in transfected muscle (C2C12) and kidney (HEK 293T) cells, producing a submaximal transcriptional response (1.8- to 2.5-fold activation) compared with rosiglitazone (7.4- to 13-fold activation). Additionally, troglitazone antagonizes rosiglitazone-stimulated PPAR-gamma transcriptional activity. Limited protease digestion of PPAR-gamma suggests conformational differences in the receptor bound to troglitazone versus rosiglitazone. Consistent with this finding, an in vitro coactivator association assay demonstrated that troglitazone-bound PPAR-gamma recruited the transcriptional coactivators p300 and steroid receptor coactivator 1 less efficiently than rosiglitazone-bound receptor. In contrast to these observations, troglitazone behaves as a full agonist of PPAR-gamma in 3T3L1 adipocytes. Two-dimensional protein gel electrophoresis demonstrated that troglitazone and rosiglitazone regulated distinct but overlapping sets of genes in several cell types. Thus, troglitazone may behave as a partial agonist under certain physiological circumstances and as a full agonist in others. These differences could be caused by variations in the amount of specific cofactors, differences in PPAR response elements, or the presence of different isoforms of PPAR-gamma.


Reproductive Toxicity and Life History Study of Silver Nanoparticle Effect, Uptake and Transport in Arabidopsis thaliana.
Concerns about nanotechnology have prompted studies on how the release of these engineered nanoparticles impact our environment. Herein, the impact of 20 nm silver nanoparticles (AgNPs) on the life history traits of Arabidopsis thaliana was studied in both above- and below-ground parts, at macroscopic and microscopic scales. Both gross phenotypes (in contrast to microscopic phenotypes) and routes of transport and accumulation were investigated from roots to shoots. Wild type Arabidopsis growing in soil, regularly irrigated with 75 μg/L of AgNPs, did not show any obvious morphological change. However, their vegetative development was prolonged by two to three days and their reproductive growth shortened by three to four days. In addition, the germination rates of offspring decreased drastically over three generations. These findings confirmed that AgNPs induce abiotic stress and cause reproductive toxicity in Arabidopsis. To trace transport of AgNPs, this study also included an Arabidopsis reporter line genetically transformed with a green fluorescent protein and grown in an optical transparent medium with 75 μg/L AgNPs. AgNPs followed three routes: (1) At seven days after planting (DAP) at S1.0 (stages defined by Boyes et al. 2001 [41]), AgNPs attached to the surface of primary roots and then entered their root tips; (2) At 14 DAP at S1.04, as primary roots grew longer, AgNPs gradually moved into roots and entered new lateral root primordia and root hairs; (3) At 17 DAP at S1.06 when the Arabidopsis root system had developed multiple lateral roots, AgNPs were present in vascular tissue and throughout the whole plant from root to shoot. In some cases, if cotyledons of the Arabidopsis seedlings were immersed in melted transparent medium, then AgNPs were taken up by and accumulated in stomatal guard cells. These findings in Arabidopsis are the first to document specific routes and rates of AgNP uptake in vivo and in situ.


Long-term salvageability for patients with locally recurrent soft-tissue sarcomas.
Between 1971 and 1988, 39 patients were referred because of local recurrence of soft-tissue sarcomas and data from their patient records were analyzed to determine the parameters governing local recurrence. Mean follow-up was 11.1 years, with a mean time to local recurrence of 22 months. Twenty-one patients had local recurrence only, without metastatic disease. Salvage was provided for 14 (67%) of these patients after reexcision of local recurrence, and all 14 patients remained free of disease (mean follow-up, 112 months). We conclude that (1) excisional biopsy of tumors larger than 3 cm leads to potential contamination of clean tissue planes, limits ability to achieve an adequate margin of resection, and may compromise the definitive excision, and (2) in patients with local recurrence only, there is a high rate of long-term salvage (67% for follow-up of 9.3 years) after radical compartmental excision with or without postoperative radiation therapy.


Catching and Correcting Unreported, Under-Reported Accidents (Near-Misses) among Healthcare Provider in Thailand.
Latent errors in an incident reporting system pose threats to accident and near-miss prevention in hospitals. The aims of this study were to gain insight into the incident reporting system by exploring and investigating the refinement of unreported and under-reported (near-miss) patterns and by estimating under-reported annual hospital accidents over three months in one hospital. Sequential mixed-method research was undertaken using both qualitative and quantitative approaches. 120 health care providers were selected from 13 departments of a selected study hospital. Self-reported questionnaires, information from annual reports and focus group interviews among stakeholders were employed. Based on a quantitative mixed-model approach, estimation of lost cases from near-miss incidents was made. In 2015, 20% of accidents had been reported to the hospital center while under-reported accidents and near-miss incidents by self-report over 3 months equaled 18% and 25.9%, respectively. Recent trends were positive, driven by changing values about incident reporting. However, confusion and fear still remain among practitioners about near-miss reporting due to old beliefs. This study confirms that incident reporting needs improvement so that there is an enhanced organizational culture of safety, raised awareness for individual reporting, and recovery of lost cases using mixed-model estimation of near-misses.


Artifacts in polarization-sensitive optical coherence tomography caused by polarization mode dispersion.
Polarization mode dispersion (PMD) severely degrades images of biological tissue measured with polarization-sensitive optical coherence tomography. It adds a bias to the local retardation value that can be spatially confined, resulting in regions of seemingly high sample birefringence that are purely artificial. Here, we demonstrate and analyze this effect, both experimentally and with numerical simulations, and show that artifacts can be avoided by limiting the system PMD to less than the system axial resolution. Even then, spatial averaging over a dimension larger than that characteristic of speckle is required to remove a PMD-induced bias of the local retardation values.


Eschar and IgM ELISA in the diagnosis of scrub typhus.
Scrub typhus is one of the leading causes of acute febrile illness in India. This study aimed to determine the best diagnostic tool for the identification of scrub typhus and study the possible association between diagnostics and clinical characteristics. Patients with fever of ≤15 days admitted to the hospital satisfying the case definition of 47 kDa quantitative polymerase chain reaction (qPCR) positivity OR scrub typhus IgM ELISA positivity along with the presence of eschar OR Scrub typhus IgM ELISA positivity along with defervescence of fever within 72 h of initiation of specific therapy were recruited. Of the 116 patients satisfying the case definition, 47 kDa qPCR was positive in 43 (37%) patients, whereas IgM ELISA was positive in 104 (90%) patients and eschar was seen in 59 (51%) patients. The median duration of fever was 7.5 days (interquartile range 6-10 days). Multiorgan dysfunction syndrome (MODS) was described in 44 (37.9%) patients. Two patients (1.8%) succumbed to the illness. Presence of eschar and IgM ELISA positivity were detected in 106 (91%) cases. Scrub typhus, even with MODS, has low mortality because of immediate institution of specific therapy due to physician awareness. The presence of eschar and IgM ELISA positivity can be used to detect a majority of cases of scrub typhus.


Ion Microbeam Analyses of Dust Particles and Codeposits from JET with the ITER-Like Wall.
Generation of metal dust in the JET tokamak with the ITER-like wall (ILW) is a topic of vital interest to next-step fusion devices because of safety issues with plasma operation. Simultaneous Nuclear Reaction Analysis (NRA) and Particle-Induced X-ray Emission (PIXE) with a focused four MeV 3He microbeam was used to determine the composition of dust particles related to the JET operation with the ILW. The focus was on "Be-rich particles" collected from the deposition zone on the inner divertor tile. The particles found are composed of a mix of codeposited species up to 120 μm in size with a thickness of 30-40 μm. The main constituents are D from the fusion fuel, Be and W from the main plasma-facing components, and Ni and Cr from the Inconel grills of the antennas for auxiliary plasma heating. Elemental concentrations were estimated by iterative NRA-PIXE analysis. Two types of dust particles were found: (i) larger Be-rich particles with Be concentrations above 90 at% with a deuterium presence of up to 3.4 at% and containing Ni (1-3 at%), Cr (0.4-0.8 at%), W (0.2-0.9 at%), Fe (0.3-0.6 at%), and Cu and Ti in lower concentrations and (ii) small particles rich in Al and/or Si that were in some cases accompanied by other elements, such as Fe, Cu, or Ti or W and Mo.


Prevention and management of chronic disease: a litmus test for health-systems strengthening in low-income and middle-income countries.
National health systems need strengthening if they are to meet the growing challenge of chronic diseases in low-income and middle-income countries. By application of an accepted health-systems framework to the evidence, we report that the factors that limit countries' capacity to implement proven strategies for chronic diseases relate to the way in which health systems are designed and function. Substantial constraints are apparent across each of the six key health-systems components of health financing, governance, health workforce, health information, medical products and technologies, and health-service delivery. These constraints have become more evident as development partners have accelerated efforts to respond to HIV, tuberculosis, malaria, and vaccine-preventable diseases. A new global agenda for health-systems strengthening is arising from the urgent need to scale up and sustain these priority interventions. Most chronic diseases are neglected in this dialogue about health systems, despite the fact that non-communicable diseases (most of which are chronic) will account for 69% of all global deaths by 2030 with 80% of these deaths in low-income and middle-income countries. At the same time, advocates for action against chronic diseases are not paying enough attention to health systems as part of an effective response. Efforts to scale up interventions for management of common chronic diseases in these countries tend to focus on one disease and its causes, and are often fragmented and vertical. Evidence is emerging that chronic disease interventions could contribute to strengthening the capacity of health systems to deliver a comprehensive range of services-provided that such investments are planned to include these broad objectives. Because effective chronic disease programmes are highly dependent on well-functioning national health systems, chronic diseases should be a litmus test for health-systems strengthening.


Hemorrhage vs rethrombosis after thrombolysis for acute myocardial infarction.
To determine whether or not the timing of heparin infusion affects either bleeding or reocclusion following intracoronary streptokinase for acute myocardial infarction, heparin was infused immediately after streptokinase in 89 patients and was delayed for 12 hours in the subsequent 93. Bleeding occurred in 22 immediate-heparin patients and was major in five (one fatal); there were 14 hemorrhages in the delayed-heparin group, all minor. At discharge, reocclusions were observed in 18% (12/68) of immediate-heparin patients, and 11% (3/27) of the latter. Bioassayed fibrinogen levels displayed sustained depression regardless of bleeding for 20 hours after streptokinase; however, defibrinogenation measured by immunoassay was much less striking. This suggests that high levels of fibrinogen degradation products spuriously affect the bioassay of fibrinogen. We conclude that bleeding is related to the anticoagulant effects of fibrinogen degradation products interacting with heparin, and may be largely independent of hypofibrinogenemia. Delaying heparin for 12 hours may decrease the risk of bleeding while little affecting the risk of reocclusion.


Interpretation and expectation in childhood anxiety disorders: age effects and social specificity.
Theory and treatment for childhood anxiety disorders typically implicates children's negative cognitions, yet little is known about the characteristics of thinking styles of clinically anxious children. In particular, it is unclear whether differences in thinking styles between children with anxiety disorders and non-anxious children vary as a function of child age, whether particular cognitive distortions are associated with childhood anxiety disorders at different child ages, and whether cognitive content is disorder-specific. The current study addressed these questions among 120 7-12 year old children (53% female) who met diagnostic criteria for social anxiety disorder, other anxiety disorder, or who were not currently anxious. Contrary to expectations, threat interpretation was not inflated amongst anxious compared to non-anxious children at any age, although older (10-12 year old) anxious children did differ from non-anxious children on measures of perceived coping. The notion of cognitive-content specificity was not supported across the age-range. The findings challenge current treatment models of childhood anxiety, and suggest that a focus on changing anxious children's cognitions is not warranted in mid-childhood, and in late childhood cognitive approaches may be better focussed on promoting children's perceptions of control rather than challenging threat interpretations.


Electromagnetic fields and transmission properties in tapered hollow metallic waveguides.
We analyze the electromagnetic spatital distributions and address an important issue of the transmission properties of spherical transverse-electric (TE) and transverse-magnetic (TM) eigenmodes within a tapered hollow metallic waveguide in detail. Explicit analytical expressions for the spatital distributions of electromagnetic field components, attenuation constant, phase constant and wave impedance are derived. Accurate eigenvalues obtained numerically are used to study the dependences of the transmission properties on the taper angle, the mode as well as the length of the waveguide. It is shown that all modes run continuously from a propagating through a transition to an evanescent region and the value of the attenuation increases as the distance from the cone vertex and the cone angle decrease. A strict distinction between pure propagating and pure evanescent modes cannot be achieved. One mode after the other reaches cutoff in the tapered hollow metallic waveguide as the distance from the cone vertex desreases.


Fluorescent H-aggregates of an asymmetrically substituted mono-amino Zn(ii) phthalocyanine.
The photophysical properties of a newly synthesized unsymmetrically substituted zinc phthalocyanine derivative (1) bearing in its peripheral positions six n-hexylsulfanyl substituents and one amino-terminated n-hexylsulfanyl substituent were investigated. This mono-amino phthalocyanine exhibited a high tendency to form H-type aggregates in all of the investigated solvents: dichloromethane (DCM), tetrahydrofuran (THF) and dimethyl sulfoxide (DMSO). Several species of H-aggregates were present together in relatively broad concentration ranges in THF and DCM, whereas in DMSO they were observed separately depending on the concentration used. Despite the widely accepted non-emissive character of H-type dimers, the H-type aggregates of phthalocyanine 1 were highly emissive in all solvents: the fluorescence quantum yield in DMSO for the n-aggregate is equal to 0.05, whereas for the (n + 1)-aggregate it is 0.11. Upon (n + 1)-aggregation, the fluorescence lifetime of the n-aggregate increased from ca. 2.5 ns to 3.3 ns. Based on these results, the radiative lifetimes of both species were computed: 48 ns for the n-aggregate and 29 ns for the (n + 1)-aggregate. The determined oscillator strengths for the n-aggregate and the (n + 1)-aggregate in DMSO were 0.04 and 0.12, respectively. The observed emission of the H-type (n + 1)-aggregate was assigned to the radiative transition from the upper exciton state to the ground state, which could be rationalized by a constant thermal repopulation of the upper exciton state. The experimental findings were supported by theoretical calculations.


The Role of Communities in Mental Health Care in Low- and Middle-Income Countries: A Meta-Review of Components and Competencies.
Community-based mental health services are emphasized in the World Health Organization's Mental Health Action Plan, the World Bank's Disease Control Priorities, and the Action Plan of the World Psychiatric Association. There is increasing evidence for effectiveness of mental health interventions delivered by non-specialists in community platforms in low- and middle-income countries (LMIC). However, the role of community components has yet to be summarized. Our objective was to map community interventions in LMIC, identify competencies for community-based providers, and highlight research gaps. Using a review-of-reviews strategy, we identified 23 reviews for the narrative synthesis. Motivations to employ community components included greater accessibility and acceptability compared to healthcare facilities, greater clinical effectiveness through ongoing contact and use of trusted local providers, family involvement, and economic benefits. Locations included homes, schools, and refugee camps, as well as technology-aided delivery. Activities included awareness raising, psychoeducation, skills training, rehabilitation, and psychological treatments. There was substantial variation in the degree to which community components were integrated with primary care services. Addressing gaps in current practice will require assuring collaboration with service users, utilizing implementation science methods, creating tools to facilitate community services and evaluate competencies of providers, and developing standardized reporting for community-based programs.


A high throughput perfusion-based microbioreactor platform integrated with pneumatic micropumps for three-dimensional cell culture.
This study reports a new perfusion-based, micro three-dimensional (3-D) cell culture platform for high-throughput cell culture using enabling microfluidic technologies. In this work, the micro 3-D cell culture platform is fabricated based on SU-8 lithography and polydimethylsiloxane replication processes. The micro cell culture platform can maintain homogenous and stable culture environments, as well as provide pumping of multiple mediums and efficient cell/agarose (scaffold) loading functions, which allows realization of more precise and high-throughput cell culture-based assays. In this study, the design of a high-throughput medium pumping mechanism was especially highlighted. A new serpentine-shaped pneumatic micropump was used to provide the required medium pumping mechanism. Pneumatic microchannels with a varied length and U-shape bending corners were designed to connect three rectangular pneumatic chambers such that one can fine-tune the pumping rate of the S-shape micropump by using the fluidic resistance. To achieve a high-throughput medium pumping function, a pneumatic tank was designed to simultaneously activate all of the 30 pneumatic micropumps with a uniform pumping rate. Results show that the pumping rates of the 30 integrated micropumps were statistically uniform with a flow rate ranging from 8.5 to 185.1 microl h(-1), indicating the present multiple medium pumping mechanism is feasible for high-throughput medium delivery purposes. Furthermore, as a demonstration case study, 3-D culture of oral cancer cell was successfully performed, showing that the cell viability remained as high as 95% - 98% during the 48 h cell culture. As the result of miniaturization, this perfusion-based 3-D cell culture platform not only provides a well-defined and stable culture condition, but also greatly reduces the sample/reagent consumption and the need for human intervention. Moreover, due to the integrated capability for multiple medium pumping, high-throughput research work can be achieved. These traits are found particularly useful for high-precision and high-throughput, 3-D cell culture-based assay.


Quantifying single-cell secretion in real time using resonant hyperspectral imaging.
Cell communication is primarily regulated by secreted proteins, whose inhomogeneous secretion often indicates physiological disorder. Parallel monitoring of innate protein-secretion kinetics from individual cells is thus crucial to unravel systemic malfunctions. Here, we report a label-free, high-throughput method for parallel, in vitro, and real-time analysis of specific single-cell signaling using hyperspectral photonic crystal resonant technology. Heterogeneity in physiological thrombopoietin expression from individual HepG2 liver cells in response to platelet desialylation was quantified demonstrating how mapping real-time protein secretion can provide a simple, yet powerful approach for studying complex physiological systems regulating protein production at single-cell resolution.